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Implantable drainage devices in glaucoma: Quo vadis?
European Journal of Pharmaceutical Sciences 133 (2019) 1–7
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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Review
Implantable drainage devices in glaucoma: Quo vadis? ⁎
T
Khushwant S. Yadav , Sushmita Sharma Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed to be University, Mumbai, Maharashtra, India
A R T I C LE I N FO
A B S T R A C T
Keywords: Glaucoma Intraocular pressure Implantable drainage devices Ahmed glaucoma valve Valved Non-valved
Glaucoma, a gradually progressive class of either chronic eye disease or disorder, occurs due to increasing intraocular pressure. To reduce glaucoma, it is essential to stop the progression of IOP in the eye which is achieved by medical treatment, laser treatment and surgery. Profuse conventional drugs and laser surgeries are the primary go-tos for decreasing IOP. However, presently available marketed formulations using anti-glaucoma drugs have issues of either difficulty in crossing the blood retinal barrier (BRB) or lower systemic bioavailability. Hence, the drugs having lower therapeutic index would need to be administered frequently. This repeated systemic administration of high doses of drugs eventually leads to side effects, damage to the eye as well as patient noncompliance. Implants are deemed to be the suitable treatment left when such side effects are to be avoided. An eye implant is one of the choices for restoring the volume of the eye socket following evisceration and enucleation. Implantable drainage devices (IDD) aka glaucoma drainage devices (GDDs) or aqueous shunts are small reconstructive surgery devices, either solid or made of a tube fixed to an endplate. The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage opening and positioning the device properly on it. All implants are made with an objective of decreasing IOP by enhancing the fluid outflow from the eye. A critical comparison is made among different implants like Molteno: single-plate and Double-plate, Baerveldt drainage implant, Schocket implant, Ex-Press R50 implant, Ahmed glaucoma valve, Krypton implant to the latest one's including iStent, iStent inject, Hydrus, CyPass, XEN and InnFocus.
1. Introduction Glaucoma, a gradually progressive class of either chronic eye disease or disorder, occurs due to increasing intra-ocular pressure (IOP). IOP is well defined as the pressure created inside the eye which lies in the range of 10–21 mm Hg (Yan, 2011). The increased IOP, of more than 22 mm Hg is intolerant by normal eyes and ultimately the root of optic nerve injury. This continuous long term harm to optic nerve triggers failing of communication between retina and the brain leading finally to irreversible vision loss (Hertzog et al., 1996). The various factors affecting treatment of glaucoma are its causes, severity and susceptibility of patient (Gaasterland, 2004). Glaucoma is commonly associated with ocular hypertension. However, glaucoma can also occur when the intraocular pressure is normal, termed normal tension glaucoma. To reduce glaucoma, it is essential to stop the progression of IOP in the eye which is achieved by medical treatment, laser treatment and surgery (Yadav et al., 2019) Profuse conventional drugs and laser surgeries are the primary go-tos for decreasing IOP. Despite that some patients do not respond well to conventional eye drops because the medication gets absorbed on the surface layer of the eye into ⁎
conjunctiva blood vessels. In case of systemic absorption of drugs, it is necessary for the administered drug to cross BRB to arrive at posterior ocular tissue, while, to arrive at anterior tissue of the eye, it is required to cross blood aqueous barrier. Thus, these barriers are responsible for decreasing the intra-vitreal levels of lipid drugs which are poorly soluble by 10% to that of serum levels (Ghate and Edelhauser, 2006). Treatment with conventional drugs, on the other hand, has to be repeatedly administered in the target site which is eye due to their low therapeutic index which is essential to attain the desired therapeutic concentration of the drug (Nisha and Deepak, 2012). Drugs that are administered topically reaches the anterior chamber after it gets absorbed in the cornea body (Agrahari et al., 2016). The drug further reaches uvea by the aqueous flow movement and diffusion mechanism in the blood. The drug undergoes permeation via corneal epithelium by aqueous flow movement and the drug also gets absorbed via diffusion mechanism through the cornea. It is then transferred into the anterior chamber. The drug gets transported by aqueous flow and by diffusion into the blood circulation through anterior uvea. Drug molecules can permeate through the corneal epithelium by two pathways namely transcellular pathway for transportation of lipophilic drugs and
Corresponding author. E-mail addresses: [email protected], [email protected] (K.S. Yadav).
https://doi.org/10.1016/j.ejps.2019.03.007 Received 15 December 2018; Received in revised form 28 February 2019; Accepted 10 March 2019 Available online 12 March 2019 0928-0987/ © 2019 Elsevier B.V. All rights reserved.
European Journal of Pharmaceutical Sciences 133 (2019) 1–7
K.S. Yadav and S. Sharma
opening the fistula with the aid of silicon tube for draining of aqueous humor and also to curb conjunctival scarring by using endplate that maintains the potential space. Furthermore, it can bypass the BRB and also deliver onsite action. Overcoming BRB is possible because of intravitreal administration of drugs (Cholkar et al., 2013).
paracellular pathway for transporting hydrophilic drugs. The lipophilic drugs either rest in epithelial cells or progressively gets released into corneal stroma and anterior chamber. The lipophilic corneal epithelium is thus the barrier for drugs that are hydrophilic in nature. The drug finally arrives at aqueous humor and gets distributed in the iris and ciliary body (Agrahari et al., 2016). Glaucoma filtration surgery (GFS) procedure often escorts bleb formation which performs like reservoir and is analogous to other complications like bleb leakage and other infections caused as a result of formation of bleb (Chen et al., 1997, Joshi et al., 2005). Trabeculectomy, a surgical procedure is also associated with postoperative fibrosis as well as unrestricted scar formation in limbal area leading to its debacle and making implants as the tailor made surgical procedure (Broadway et al., 1998). Should one exhaust all of these methods, implants are deemed the suitable treatment left for glaucoma as they are designed to outdo the hurdles of GFS (Gedde et al., 2007). In this context the present minireview is aimed at presenting the advantages, applications and advances in the implantable drainage devices. A clear comparison between the presently available devices and cutting-edge technology in this field is presented in brief.
3. History of IDD: quo coepi? Earlier in the year 1906, Rollet and Moreau, carried out an experiment to treat absolute glaucoma where horse hair was positioned through corneal double paracentesis for removing the fluid or any gas and to drain the inflammatory cells of anterior chamber of eye. Then in the year 1912, first translimbal GDD, outlined by Zorab came into existence where silk thread was brought into play to drain the aqueous humor in the subconjunctival space (Lim et al., 1998). In 1959, Epstein introduced concept of inserting polyethene tube. Following, in the year 1969 MacDonald and Pearce made an implant by inserting silicon tube. Fig. 2 gives a pictorial presentation of major changes from 1960s to 2010 in the progress of implantable drainage devices. Subsequently, Molteno, in the year 1969 came with an idea of developing first non valved GDD which consisted of a tube devoid of a valve. Except profuse care and handling of the tube by suturing, shortfall of IOP surpasses resulting in hypotony. Hypotony is a term used in reference for IOP of 5 mm Hg and further eye collapsing. To overcome the hassle, economically and socially advanced valve came into light. Initiated and put forward in at the later year in 1976, Krupin introduced first valved GDD with characteristics preventing hypotony. Thereafter, in 1993, the model was improvised when Ahmed glaucoma valve (AGV) was introduced, designed in various shapes and sizes and in a way that the valve opened with IOP value of 8–12 mm Hg. These devices are growing over recent years and led to development of ExPress R50 (Fig. 3) along with Istent, InnFocus and AqueSys (Acosta et al., 2006; Al-Shohani, 2017).
2. Implantable drainage devices Implantable drainage devices (IDD) are small reconstructive surgery devices which create an alternate pathway for the outflow of aqueous humor in the eye. These implants are usually adapted to when there is a need for restoring the volume of the eye socket following evisceration (a cosmetic procedure where extraocular muscles and white fibrous portion of the eye called sclera are unharmed) and enucleation (a procedure involving removal of the whole eyeball (Kitzmann et al., 2003). The IDD is also known as a glaucoma drainage device (GDD) or as aqueous shunt (Glaucoma Research Foundation, 2018). Fig. 1 is a schematic representation of implantable drainage device. These devices are a solid body made up of a tube of silicone of approximate diameter of size 300 μm, fixed to an endplate of polypropylene. The one side of the tube is fixed to anterior region while the other side usually serves attachment to the plate in subconjunctival region of the eye (Saha et al., 2017). IDD work by opening the fistula with the aid of silicon tube for draining of aqueous humor and also to curb conjunctival scarring by using endplate that maintains the potential space (Ekinci et al., 2014). There are various conditions which puts implants as the favorable choice, one among them being able to bypass BRB and delivering onsite action of the administered drug. Secondly, it maintains the drug release over prolonged period. Also, in case of systemic administration, it provides minimum side-effects (Silva et al., 2010). IDD work by
4. Materials used in construction of implants IDD currently in use are solid spheres with thin body and desired length (Bene et al., 2008) made of different materials akin to penetrable polyethylene or coralloid hydroxyapatite (Baino and Potestio, 2016). Earlier, they were made of materials like glass, silk thread, acrylic, collagen, platinum, teflon, autologous lacrimal canaliculus and cartilage (Iosrjournals.org., 2018) which showed high complication rates like formation of scar near the limbus, excessive migration and erosion of conjunctiva. IDD are drug delivery systems which can be made either from degradable or non-degradable materials. The biodegradable materials include biodegradable polymers while non-biodegradable materials comprise endplates made of stainless steel, metals and non-biodegradable polymers. Biodegradable polymers are polylactide-co-glycolide acid (PLGA) (Yadav et al., 2011), silicon and polylactic acid (PLA). These biodegradable polymers are degraded (get absorbed) and do not leave any remains of the drug carrier, thereby eliminating the need for surgical removal unlike with non-biodegradable polymers where the carriers may, sometimes, accumulate and lead to many complications like cataract, hemorrhage etc. The examples of implants made off biodegradable polymers include Retisert® and IIuvien® (Del Amo and Urtti, 2008). Non-biodegradable polymers provide better prolonged release but require surgical removal of the polymers as they do no degrade inside the body. Some of the non-biodegradable polymers are polyvinyl alcohol, ethylene vinyl alcohol, etc. The examples of such type of implant include Ozurdex® and Surodex® (Haghjou et al., 2011).
Fig. 1. Schematic representation of implantable drainage device. An IDD consists of a solid body and a tube. The body is made of a tube of silicone of approximate diameter of size 300 μm which is fixed to an endplate usually made of polypropylene. (Abbreviations: IDD - implantable drainage device).
5. Mechanism of action of the implants The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage 2
European Journal of Pharmaceutical Sciences 133 (2019) 1–7
K.S. Yadav and S. Sharma
Fig. 2. History of implantable drainage devices. In the year 1969, first non valved IDD was developed which consisted of a tube devoid of a valve. Then in 1970s, single plate was introduced for better drainage but then led to side effects like aphakia. Later in 1980s double plate was introduced with improved intraocular pressure but had a complication of hypotony. Thereafter, Molteno Pressure Ridge implant emerged, followed by Molteno3 in 2000s and Molteno3s in 2010. (Abbreviations: IDD - implantable drainage device).
tolerated biomaterial, is inserted either in anterior chamber or in between the base of the iris and ciliary body called ciliary sulcus (Schnaudigel, 1990). It can also be placed in pars plana, present in uvea, portion of ciliary body. The plate is positioned on sclera typically in superior temporal quadrant. Tube serves the function of draining the fluid in the posterior region of implant (Wang and Barton, 2017). The tube allows flowing of fluid to plate placed on upper eyelid surface and thus acts as an artificial drain. The fluid is then passed through this and gets reabsorbed into the body fluids (Matthew Emanuel, 2018; Haffner et al., 2017). Nevertheless, solid sphere implantation is laborious as the sclera cavity should be wide enough to fit the sphere. An alternative method is favorable where liquefied implants can be injected by making a small incision (Yeatts et al., 2002). Implants may pose a threat of causing unwarranted injury to the eye and thereby proper handling of implant is necessary. Refusing to acknowledge the risks of surgeries, intraocular implants are outlined with a goal of producing sustained release from the polymeric material. The implant serves the advantages of bypassing the blood-retinal barrier and delivering onsite action. Very less quantity of drug is required for implantation (Bourges et al., 2006). Implants are used for managing refractory glaucoma, complicated glaucomas following keratoplasty, glaucoma succeeding injury or any trauma in the eye. Moreover, it is useful for treating congenital glaucoma, primary open angle glaucoma (POAG), neovascular glaucoma, (Sidoti et al., 1995) uveitic glaucoma (UG) (Da Mata et al., 1999) and other glaucomas where conventional treatment fails to cope.
Fig. 3. Ex-PRESS Mini glaucoma shunt. The Ex-PRESS glaucoma shunt, made of stainless steel consists of a spur and a flat backplate. The spur is designed to prevent extrusion while external backplate serves the function of preventing intrusion. The device constitutes a relief port which offers alternative pathway for outflow of aqueous humor.
6. Pathophysiology at the site of implant Fig. 4. Mechanism of action of implantable drainage devices. The figure illustrates the implantation of the ocular drainage device and its valve mechanism. The drainage tube allows the outflow of aqueous humor. The aqueous humor is drained in the body of the plate, positioned in the subconjunctival space. Valve mechanism of the device consists of elastic membranes made of silicone. These membranes are designed in such a way that in response to fluctuations in intraocular pressure, the valves open and close. As IOP extends its threshold value, the aim is to decrease the IOP Pressure difference is created because of the wider cross section of the inlet than outlet which allows opening of the valve. Reduced hypotony is observed with the decreased pressure and tension created in the silicone membrane. (Abbreviations: IOP - intraocular pressure)
When implant is positioned, fibrous capsule keeps developing over several weeks around the end plate. There is no fibroblast adhesion on the silicone material thus making IDD an important feature for its success. The aqueous humor flows from the ciliary body present in the anterior region of the eye and passes through fibrous capsule following end plate (Saha et al., 2017). It flows by the mechanism of passive diffusion to finally be flown by the lymphatic drainage system. The fibrous capsule thus serves as the important site for obstructing the aqueous humor outflow (Fig. 6). Henceforth, performance of drainage surgery is totally dependent on the breadth of the fibrous capsule and area of encapsulation. The implant surface area is an imperative factor for the long term IOP control with all the devices, as it determines the tissue response, bleb size and fibrous capsule thickness that control the pathway of aqueous via bleb wall (Glaucoma drainage devices).
opening and positioning the device properly on it. Glaucoma can be reduced mainly via two mechanisms, either by elevating the outflow of aqueous fluid or by decreasing its formation (Fig. 4). All implants are made with an objective of decreasing IOP by enhancing the aqueous fluid outflow from the eye. In standard surgery procedures, GFS, like trabeculectomy or sclerostomy, a minute drainage hole is created in the sclera (Karmel, 2004). This hole allows the fluid to drain in the delicate covering of the eye, conjunctiva. Considering implant surgery, the device requires positioning in the upper or lower eyelid, preferably cornea-sclera cavity (Ozqur et al., 2005) or under the conjunctiva. Irrespective of the type of implant, a tube of silicone, a well-
7. Types of implants and their advances There are two types of distinguishing implants, valved and non valved implants. Non valved also called non-restrictive implants are IDDs which consist of a tube made of silicon and is joined to an endplate. The endplate represents a surface for the formation of bleb. Non valved implants should be blocked for short term to prevent hypotony 3
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prior to development of adequate fibrosis near the plate. In order to prevent hypotony, valved devices play a productive role as they instantly allow the flow after implantation (Brandt et al., 2018). Non-valved implants can be further divided as Single-plate Molteno (SPM), Double-plate Molteno (DPM), Baerveldt drainage implant (BDI), Schocket implant, Ex-Press R50 implant. Single-plate Molteno is the implant in which a silicone tube is fixed to 135 mm2 endplate made of polypropylene. Double-plate Molteno (DPM) is similar to that of a single plate Molteno except the fact that there is a second end plate fixed to either right side or left side of the existing initial endplate. Thus, the surface area is twice the single-plate Molteno. The size of the silicone tube is 10 mm (Schwartz et al., 2006). The BDI when compared to DPM has benefit of easy insertion as it requires one quadrant for dissection. As well, the silicon plate, less inflammatory and more bendable than polypropylene 6 owes easy handling and more flexibility in the quadrant. However, BDI has disadvantages like heterotropia, diplopia and motility restriction, because of large implant size (Smith et al., 1993). BDI consists of a pliable, soft silicone endplate with sizes 250 mm2, 350 mm2 and also 500 mm2 impregnated with barium fixed to silicone tube (Schwartz et al., 2006). Baerveldt posed a slight risk of emptying the anterior chamber (Smith et al., 1993). Schocket implant is a tube made of silicone where its one end is joined to the anterior chamber while the other is tied beneath retinal encircling band. Ex-Press R50, an implant made of stainless steel is 2–3 mm long and has 0.4 mm diameter tube, which helps in attachment of the anterior chamber and intrascleral space. Initially, it was inserted under the conjunctiva but currently they are placed under the sclera in order to avoid further filtrations (Fig. 5). (Huerva et al., 2016; Bissig et al., 2010; De Feo et al., 2009). Valved, also called restrictive implants comprises of AGV, where the end plate is scarab shaped and is formed of either silicone or polypropylene. The silicone tube is joined to the body of propylene. The valve is made in a way that it opens when IOP measures 8 mm Hg. AGV in analogy with BDI showed higher hypertension rate. Also, increase in IOP was observed after 1–2 month of implantation. In regards to bleb formation, AGV had more effect than BDI. However, for hypotony and choroidal shedding, BDI raised the complications following ligature (Syed et al., 2004). Krupin slit valve (KSV) is another type of valved implants where the silicone tube is attached to oval silastic endplate. The endplate has a surface area of 180 mm2. There are some GDDs with varying resistance such as Molteno dual ridge (MDR) and Baerveldt bioseal implant. The plate's top is divided into two separate spaces in the molten dual
ridge device in order to limit the initial drainage area. Aqueous escapes into the narrow channel that separates these two concentric ridges, but it also has to overcome the resistance from conjunctival tissue apposition in order to flow further. This is achieved later by partially encapsulating the plate element which results in the overlying tissue clearing off of the inner pressure ridge, allowing an unrestricted aqueous flow into the overlying space. In the modified Baerveldt implant, the ‘Bioseal’ element is opposed to the sclera having absorbable sutures to secure early flow resistance, prohibiting initial aqueous to escape from beneath. The common problem with both the approaches is, much like trabeculectomy, the poor tissue apposition. There is varying early flow resistance and unpredictable initial IOP levels (Kim et al., 2016). MDR implant obstructs the drainage area. The top region of the plate is separated into two portions with the help of a V-shaped ridge. Baerveldt device consists of an endplate of silicone impregnated with barium with a surface area of 250 mm2 or 350 mm2 (Singh et al., 2013; Schwartz et al., 2006) (Table 1). 8. Advances and developments in implants: quo nunc? Traditional surgery, in defiance of its efficacy, leads to side effects such as hypotony, endophthalmitis, hemorrhage, surface thinning and scarring, implant exposure, infection of implant (Zhang et al., 2015), eye surface diseases and socket syndrome (Vagefi et al., 2011). To overcome the side effects while maintaining efficacy, current targets are to secure the Minimally Invasive Glaucoma (MIGS) procedures. These procedures are found to be more effective than traditional method of surgery as it gives importance to patient safety. In addition, they are more effective in reducing IOP (Ansari, 2017). While giving a look through published articles, it was found that most of the implants are yet to be approved. The reason contributing to this statement is ‘lack of knowledge’ for differentiating types of implants. Also, there is a lack of randomized clinical trials which is essential to evaluate the long term complications and efficacies of different implants. MIGS implants can then come into account and serve better. Considering, the type of flow, they are classified into three main implants, first are the implants that enhance trabecular outflow through trabecular meshwork implants. Second one increases the uveoscleral outflow through suprachoroidal route by developing a drainage path in the sub-conjunctival region and third type of implants creates subconjuctival drainage pathway. These are summarized in the Table 2 (Ansari, 2017). 9. Pre-clinical studies on IDDs The potency and correlation of non-valved implants with that of two valved implants so to treat recalcitrant glaucoma was well executed by Taglia et al. (2002) where the study compared DPM with KSV and AGV. The reports concluded that DPM implantation maintained the IOP in the range of 5–15 mm Hg when compared to AGV. The success rates were 80% for DPM implanted patients at the end of a year followed by KSV with 39% and lastly AGV with 35% success rate. Howbeit, the study summed up that the complications were least for AGV patients. The efficacy of intracameral implantation in rabbits for long term therapy of glaucoma was well understood by Kim et al. (2016) where an implant of polycaprolactone loaded with selective EP2 agonist DE-117 was developed. The single device for drug delivery offered outcomes like significant reduction in IOP in rabbits for around 23 weeks. Also, it maintained the concentration of the drug DE-117 in the target tissue until 6 months at the rate of 0.5 μg/day and thus circumvented patient compliance. Evan et al. came with a concept of creating sustained duo drug delivery systems with a combination of non-biodegradable system and biodegradable system. Poly(2-hydroxyethyl methacrylate) [P (HEMA)] with MMC as non-biodegradable polymer while PLGA with 5fluorouracil (5-FU) as biodegradable polymer constituting MMC or devoid of MMC were used for the same. The study focused to report the
Fig. 5. Conjunctiva under normal operation and encapsulation. The drainage implant cross section focuses on the development of the fibrous capsule tissue, bleb, with time. The bleb acts as a pool for aqueous humor. Under normal condition, the IOP is under control and there is reduced bleb thickness whereas in some cases there is formation of dense layered collagen as depicted on the right side in the figure. Fibrous encapsulated bleb (dense layer of collagen) shows higher IOP because of the reduced capacity of the device to drain aqueous humor. (Abbreviations: IOP - intraocular pressure). 4
European Journal of Pharmaceutical Sciences 133 (2019) 1–7
K.S. Yadav and S. Sharma
Table 1 Classification of intraocular implants for treating glaucoma (Al-Shohani, 2017). Implants
Valved/non-valved
Description
Size
Single-plate Molteno Double-plate Molteno Baerveldt drainage implant
Non-valved Non-valved Non-valved
Silicone tube + single polypropylene endplate Silicone tube + double polypropylene endplate Silicone tube + silicone impregnated with barium endplate
Schocket implant Ex-Press R50 implant Ahmed glaucoma valve Krupin-slit valve
Non-valved Non-valved Valved Valved
Silicone tube Tube of stainless steel, no end plate Silicone tube + polypropylene endplate Silicone tube + silicone endplate
340 μm-inner diameter of tube, 135 mm2-endplate 340 μm-inner diameter of tube, 268 mm2-endplate 300 μm-inner diameter of tube, 250 mm2, 350 mm2 and 500 mm2-endplates. Width 4 mm and 6 mm, diameter- 24 mm 2–3 mm long, 0.4 mm diameter tube 300 μm-inner diameter of tube, 185 mm2-endplate 300 μm-inner diameter of tube, 180 mm2-endplate
Table 2 An insight on implants approved by US FDA. Implant types based on flow
Implant
Materials
Dimensions
Examples
US FDA approval status
Trabecular
iStent
Coated with heparin
1 mm × 0.3 mm
iStent inject
Non-ferromagnetic, made of titanium Alloy of nickel and titanium Nitinol Polymers of amide
230 μm × 360 μm
Glaukos Corp. (USA) Glaukos Corp. (USA) Ivantis Inc. (USA) Alcon (USA)
Approved in June 2012 (Investors.glaukos.com, 2019). Approved in June 2018 (Fda.gov, 2019a, 2019b) Approved in August 2018 (Fda.gov, 2019a, 2019b). Approved in July 2016 (Medscape., 2019). Approved in November 2016 (Glaucoma Research Foundation, 2019).
Hydrus Uveo-scleral
CyPass
Subconjunctival ab interno
XEN
Gelatin in crosslinkage with glutaraldehyde
8 mm in length 6.35 mm in length, external diameter510 μm, 300 μm-internal diameter 6 mm in length, 45 μm–internal diameter
Allergen (Ireland)
Fig. 7. Part of plant body in action under applied magnetic field. Magneto elastic actuators are linked to IDDs as they can control cellular adhesion on the surface of the body of implant. These actuators are fixed within the IDD or attached to it prior to the surgery. The stresses produced via vibration of the actuator reduce adhesion of fibrous tissue and also obstructs encapsulation. Thus, it aids in proper management of IOP because of easy outflow of aqueous humor. The actuator constitutes paddles and spring. The vibrations occur in the paddle and causes drainage of aqueous humor. The springs are attached to the anchor. (Abbreviations: IDD - implantable drainage device, IOP - intraocular pressure).
Fig. 6. Drainage tube with micro actuators. Implantable drainage device along with microactuators, vibrates on exposure to magnetic field.
effect of MMC as fibrosis (thickening of connective tissue as a consequence of injury) reducing agent when connected to AGV in albino rabbit model were 48 rabbits were taken and then divided into equal groups of 6 based on polymers. It was observed that thickness of the bleb wall was significantly decreased in systems with combo of nonbiodegradable and biodegradable polymers. Evan et al. accomplished his desired aim and proved it successfully when the system displayed reduced fibrosis and no harmful effects (Schoenberg et al., 2015).
Sheybani et al. revealed the IOP reduction from 23 mm Hg initially to IOP of 14 mm Hg at the end of year. The mean IOP reduction was found to be 36.4%, slightly higher than the above case. Also, XEN 45 attained a steady-state pressure at 7.56 mm Hg at the rate of 2.5 μL/min (Sheybani et al., 2015). In another research, Moore et al. (2015) scrutinized the aftermath of placing sustained release fluocinolone acetonide drainage implant (Retisert) approved by United States Food and Drug Administration (FDA) in the year 2005, in combination with an AGV in eyes of patients suffering from UG and placing AGV alone in patient's eyes suffering from either POAG or UG. The surgery was said to accomplish the desired goal only when IOP was in the range of 5–18 mm Hg. The duration for mean IOP reduction was higher in Retisert eyes of patients suffering from UG than patients suffering from POAG. Ultimately, Moore et al.
10. Clinical studies on IDDs Galal et al. (2017) evaluated XEN, Aquesys, gelmicrostents to know its effectiveness in treating POAG. In the following procedure, there was decline in IOP from 10 to 24 mm Hg to 2–20 mm Hg in first week. And finally by the end of a year, the IOP dropped to 6–18 mm Hg. However, there was a complication of choroidal detachment observed. The evaluation concluded that XEN implant is very effective in significantly reducing IOP for a period of 1-year minimum follow up and thus treating POAG. A similar study was performed which aimed at describing fluidics of non valved glaucoma and IOP reduction. Studies of 5
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Acknowledgement
interpreted that Retisert in combination with AGV implantation had greater impact on duration of action than AGV alone in the eyes of patients with UG or POAG.
The authors are thankful to Mr. Viral Bakhai and Ms. Shweta Sharma for their valuable help in drawing and editing the figures.
11. IDD: where are these devices going (quo vadis)? References 11.1. Regulatory status Acosta, A.C., Espana, E.M., Yamamoto, H., Davis, S., Pinchuk, L., Weber, B.A., Orozco, M., Dubovy, S., Fantes, F., Parel, J.M., 2006. A newly designed glaucoma drainage implant made of poly (styrene-b-isobutylene-b-styrene): biocompatibility and function in normal rabbit eyes. Arch. Ophthalmol. 124 (12), 1742–1749. Agrahari, V., Mandal, A., Agrahari, V., Trinh, H.M., Joseph, M., Ray, A., Hadji, H., Mitra, R., Pal, D., Mitra, A.K., 2016. A comprehensive insight on ocular pharmacokinetics. Drug delivery and translational research 6 (6), 735–754. Al-Shohani, A.D.H., 2017. Hydrogel Formulations for Ophthalmic Delivery. Doctoral dissertation. UCL (University College London). Ansari, E., 2017. An update on implants for minimally invasive glaucoma surgery (MIGS). Ophthalmol Therapy 6 (2), 233–241. Baino, F., Potestio, I., 2016. Orbital implants: state-of-the-art review with emphasis on biomaterials and recent advances. Mater SciEng C Mater Biol Appl. 69, 1410–1428 Dec 1. (pmid: 27612842). Bene, E.A., Morrill, T.J., Mulhern, M.B., Wandel, T.L., Taylor, J.B. and Mir, L., Becton Dickinson and Co, 2008. Ocular implant and methods for making and using same. U. S. Patent Application 12/050,346. Bissig, A., Feusier, M., Mermoud, A., Roy, S., 2010. Deep sclerectomy with the ex-PRESS X-200 implant for the surgical treatment of glaucoma. Int. Ophthalmol. 30 (6), 661–668. Bourges, J.L., et al., 2006. Intraocular implants for extended drug delivery: therapeutic applications. Adv. Drug Deliv. Rev. 58, 1182–1202. Brandt, J.D., Hammel, N., Fenerty, C., Karaconji, T., 2018. Glaucoma drainage devices. In: Grajewski, A., Bitrian, E., Papadopoulos, M., Freedman, S. (Eds.), Surgical Management of Childhood Glaucoma. Springer, Cham. Broadway, D.C., Grierson, I., Hitchings, R.A., 1998. Local effects of previous conjunctival incisional surgery and the subsequent outcome of filtration surgery. Am J. Ophthalmol. 125 (6), 805–818. Chen, P.P., Yamamoto, T., Sawada, A., Parrish II, R.K., Kitazawa, Y., 1997. Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese Glaucoma societies. J. Glaucoma 6 (3), 192–196. Cholkar, K., Patel, S.P., Vadlapudi, A.D., Mitra, A.K., 2013. Novel strategies for anterior segment ocular drug delivery. J. Ocul. Pharmacol. Ther. 29 (2), 106–123. Da Mata, A., Burk, S.E., Netland, P.A., Baltatzis, S., Christen, W., Foster, C.S., 1999. Management of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology 106, 2168–2172. De Feo, F., Bagnis, A., Bricola, G., Scotto, R., Traverso, C.E., 2009. Efficacy and safety of a steel drainage device implanted under a scleral flap. Canadian Journal of Ophthalmology/Journal Canadiend'Ophtalmologie 44 (4), 457–462. Del Amo, E.M., Urtti, A., 2008. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov. Today 13 (3–4), 135–143. Ekinci, M., Çagatay, H.H., Ceylan, E., Keles, S., Koban, Y., Gokce, G., Huseyinoğlu, U., Ozcan, E., Oba, M.E., 2014. Reduction of conjunctival fibrosis after trabeculectomy using topical α-lipoic acid in rabbit eyes. J. Glaucoma 23 (6), 372. Fda.gov, 2018. [online] Available at. https://www.fda.gov/downloads/MedicalDevices/ NewsEvents/WorkshopsConferences/UCM390340.pdf, Accessed date: November 2019. Fda.gov, 2019a. Hydrus® Microstent - P170034. [online] Available at. https://www.fda. gov/MedicalDevices/ProductsandMedicalProcedures/ DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm620440.htm. Fda.gov, 2019b. iStent Inject Trabecular Micro-Bypass System (Model G2-M-IS) – P170043. [online] Available at. https://www.fda.gov/medicaldevices/ productsandmedicalprocedures/deviceapprovalsandclearances/recentlyapproveddevices/ucm612792.htm. Gaasterland, D.E., 2004. Advanced glaucoma. In: Higginbotham, E.J., Lee, D.A. (Eds.), Clinical Guide to Glaucoma management. Butterworth Heinemann, Woburn, MA, pp. 171–182. Galal, A., Bilgic, A., Eltanamly, R., Osman, A., 2017. XEN glaucoma implant with mitomycin C 1-year follow-up: result and complications. J. Ophthalmol. 2017. Gedde, S.J., Schiffman, J.C., Feuer, W.J., Herndon, L.W., Brandt, J.D., Budenz, D.L., Tube Versus Trabeculectomy Study Group, 2007. Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J. Ophthalmol. 143 (1), 9–22. Ghate, D., Edelhauser, H.F., 2006. Ocular drug delivery. Expert opinion on drug delivery 3 (2), 275–287. Glaucoma Research Foundation, 2018. Glaucoma Implant Surgery. [online] Available at. https://www.glaucoma.org/treatment/glaucoma-implants.php, Accessed date: October 2019. Glaucoma Research Foundation, 2019. Allergan receives FDA approval for XEN Glaucoma Treatment System. [online] Available at. https://www.glaucoma.org/news/ allergan-receives-fda-approval-for-new-xen-glaucoma-treatment-system.php. Haffner, D.S., Cogger, J.J., Kalina, C.R. and Crimaldi, D.D., Glaukos Corp, 2017. System and method for delivering multiple ocular implants. U.S. Patent 9,554,940.) Haghjou, N., Soheilian, M., Abdekhodaie, M.J., 2011. Sustained release intraocular drug delivery devices for treatment of uveitis. J. Ophthalmic Vis. Res. 6 (4), 317–329. Hertzog, L.H., Albrecht, K.G., LaBree, L., Lee, P.P., 1996. Glaucoma care and conformance with preferred practice patterns: examination of the private, community-based ophthalmologist. Ophthalmology 103 (7), 1009–1013.
The FDA has grouped medical devices mainly into 3 classes, namely, class I, II and class III. A class III device is elaborated as devices which supports or comforts human life and is of prime importance in mitigating diseases and henceforth is epitome of highest regulation. The safety and efficacy of these devices are maintained in application called premarket approval. GDD's are classified under class III where FDA acquires 51O(k) application. The implantable devices which are currently approved are GlaukosiStent and AGI GDD. Many of GDD's are under investigation which requires premarket approval under the category of safety and also to meet the demands of effectiveness (Fda.gov., 2018). 11.2. Recent landmarks achieved The IDD has waffling degrees of success because of accumulation of microorganism on the device either during or after implantation, more precisely termed biofouling. Therefore, the latest IDD, created by Hyowon Lee, aimed to treat glaucoma and have grown reputation as it combats the biofouling by using concept of advanced microtechnology. The IDD has ability to clear itself from adverse bio buildup. The drainage tube is made of magnetic nickel microactuators which on exposure to magnetic field vibrate (Fig. 6, 7). These vibrations flush out the fluid along with the biomaterials built up in the tube (Service, 2019). 11.3. Concluding remarks IDD's have been popular in decreasing the IOP in eyes for patients with failed GFS. IDD's and their clinical trials have taken a great leap in the field of glaucoma over the years and these advances will set objectives for future. Until now, numerous adjustments have been made in the design, size and material of the implant as per patient's comfort. Many factors are responsible in throwing light upon this area with the involvement of technologies like advance sensors, micro technology and use of micro actuators. The field of science is looking forward to the implication of IDD in coming years for innovation and advance inventions in clinical management leading to the betterment of glaucoma patients. At present, IDD's is a part of clinical trials which focuses on forming a thinner capsule with outstanding hydraulic conductivity. It stands on the rationale of changing the design of the frequently used implantable drainage devices from a common plate design to a cylindrical form for achieving marked down tension on the fibrous capsule. The IDD's are newly designed with an objective of producing minimal side effects and more foreseeable control over IOP. The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage opening and positioning the device properly on it. Safety and efficacy parameters with respect to adverse effect management have been taken care of from the initiation of implants by emphasizing on the prevention of adverse events. Although, some rare and uncommon complications like bleeding inside the eye, fluid building inside the retina, eye infection may result. Tube related complications occur if not placed properly and cause swelling of cornea. Most of the side effects set right with time yet unfortunately glaucoma is irreversible blindness. Wherefore, the reason for implanting the device is for a preventive cause. Careful implanting of device is therefore required to minimize the postoperative complications. 6
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rabbit model. Translational vision science & technology 4 (3), 4. Schwartz, K.S., Lee, R.K., Gedde, S.J., 2006. Glaucoma drainage implants: a critical comparison of types. Curr. Opin. Ophthalmol. 17 (2), 181–189. Service, P, 2019. Purdue's giant leap toward personalized medicine helps eyes drain themselves for glaucoma patients. [online] Purdue.edu. Available at. https://www. purdue.edu/newsroom/releases/2018/Q4/purdues-giant-leap-toward-personalizedmedicine-helps-eyes-drain-themselves-for-glaucoma-patients.html. Sheybani, A., Reitsamer, H., Ahmed, I.I.K., 2015. Fluid dynamics of a novel micro-fistula implant for the surgical treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 56 (8), 4789–4795. Sidoti, P.A., Dunphy, T.R., Baerveldt, G., LaBree, L., Minckler, D.S., Lee, P.P., et al., 1995. Experience with the Baerveldt glaucoma implant in treating neovascular glaucoma. Ophthalmology 102, 1107–1118. Silva, G.R.D., Fialho, S.L., Siqueira, R.C., Jorge, R., Júnior, C., da Silva, A., 2010. Implants as drug delivery devices for the treatment of eye diseases. Brazilian Journal of Pharmaceutical Sciences 46 (3), 585–595. Singh, P., Kuldeep, K., Tyagi, M., Sharma, P.D., Kumar, Y., 2013. Glaucoma drainage devices. Journal of Clinical Ophthalmology and Research 1 (2), 77. Smith, S.L., Starita, R.J., Fellman, R.L., Lynn, J.R., 1993. Early clinical experience with the Baerveldt 350-mm2 glaucoma implant and associated extraocular muscle imbalance. Ophthalmology 100, 914–918. Syed, H.M., Law, S.K., Nam, S.H., et al., 2004. Baerveldt-350 implant versus Ahmed valve for refractory glaucoma: a case-controlled comparison. J. Glaucoma 13, 38–45. Taglia, D.P., Perkins, T.W., Gangnon, R., Heatley, G.A., Kaufman, P.L., 2002. Comparison of the Ahmed glaucoma valve, the Krupin eye valve with disk, and the double-plate Molteno implant. J. Glaucoma 11 (4), 347–353. Vagefi, M.R., McMullan, T.F., Burroughs, J.R., Georgescu, D., McCann, J.D., Anderson, R.L., 2011 Mar-Apr. Orbital augmentation with injectable calcium hydroxylapatite for correction of postenucleation/evisceration socket syndrome. OphthalPlastReconstr Surg 27 (2), 90–94 (pmid:20683373). Wang, J., Barton, K., 2017. Aqueous shunt implantation in glaucoma. Taiwan journal of ophthalmology 7 (3), 130. Yadav, K.S., Jacob, S., Sachdeva, G., Sawant, K.K., 2011. Intracellular delivery of etoposide loaded biodegradable nanoparticles: cytotoxicity and cellular uptake studies. J. Nanosci. Nanotechnol. 11 (8), 6657–6667. Yadav, K.S., Rajpurohit, R., Sharma, S., 2019. Glaucoma: current treatment and impact of advanced drug delivery systems. Life Sci. 221, 362–376. Yan, J., 2011. Conf. Proc. IEEE Eng. Med. Biol. Soc. Boston, MA. Yeatts, R.P., Grim, W., Stanton, C., Curry, C., 2002. Injectable hydroxyapatite paste as an option for ocular implantation after evisceration. Ophthalmology 109 (11), 2123–2128 Nov. (pmid:12414426). Zhang, Y., Zhang, M.N., Wang, X., Chen, X.F., 2015. Removal of the eye in a tertiary care center of China: a retrospective study on 573 cases in 20 years. Int J Ophthalmol. 8 (5), 1024–1030 Oct 18. (pmid:2655822).
Huerva, V., Soldevila, J., Ascaso, F.J., Lavilla, L., Muniesa, M.J., Sánchez, M.C., 2016. Evaluation of the Ex-PRESS® P-50 implant under scleral flap in combined cataract and glaucoma surgery. International journal of ophthalmology 9 (4), 546. Investors.glaukos.com, 2019. FDA approval of the istent trabecular micro-bypass. [online] Available at. http://investors.glaukos.com/investors/press-releases/pressrelease-details/2012/FDA-Approval-Of-The-iStent-Trabecular-MicroBypass/default. aspx. Iosrjournals.org, 2018. [online] Available at. http://iosrjournals.org/iosr-jdms/papers/ Vol16-issue5/Version-5/F1605052328.pdf, Accessed date: November 2019. Joshi, A.B., Parrish, R.K.I.I., Feuer, W.F., 2005. 2002 Survey of the American Glaucoma Society: practice preferences for glaucoma surgery and antifibrotic use. J. Glaucoma 14 (2), 172–174. Karmel, M., 2004. Filtering surgery takes a new direction: will it revolutionize the field? EyeNet 8, 33–36. Kim, J., Kudisch, M., Mudumba, S., Asada, H., Aya-Shibuya, E., Bhisitkul, R.B., Desai, T.A., 2016. Biocompatibility and pharmacokinetic analysis of an intracameral polycaprolactone drug delivery implant for glaucoma. Investig. Opthalmology Vis. Sci. 57, 4341–4346. Kitzmann, A.S., Weaver, A.L., Lohse, C.M., Buettner, H., Salomao, D.R., 2003. Clinicopathologic correlations in 646 consecutive surgical eye specimens, 1990–2000. Am J ClinPathol 119 (4), 594–601. Lim, K.S., Allan, B.D.S., Lloyd, A.W., Muir, A., Khaw, P.T., Lim, K.S., Allan, B.D.S., Lloyd, A.W., Muir, A., Khaw, P.T., 1998. Glaucoma drainage devices; past, present, and future. Br. J. Ophthalmol. 82 (9), 1083–1089. Matthew Emanuel, M., 2018. Glaucoma drainage implant surgery - Glaucoma Associates of Texas. online. Available at Glaucoma Associates of Texashttp:// glaucomaassociates.com/incisional-glaucoma-surgery/glaucoma-drainage-implantsurgery/, Accessed date: October 2019. Medscape, 2019. FDA updates advice on withdrawn CyPass glaucoma stent. [online] Available at. https://www.medscape.com/viewarticle/903990. Moore, D.B., Stinnett, S., Jaffe, G.J., Asrani, S., 2015. Improved surgical success of combined glaucoma tube shunt and Retisert® implantation in uveitic eyes: a retrospective study. Ophthalmol Therapy 4 (2), 103–113. Nisha, S., Deepak, K., 2012. An insight to ophthalmic drug delivery system. International Journal of Pharmaceutical Studies Research 3 (2), 9–13. Ozqur, O.R., Akcay, L., Doğan, O.K., 2005 Jan. Evisceration via superior temporal sclerotomy. Am J. Ophthalmol. 139 (1), 78–86 (pmid:15652831). Saha, Bhawesh, Kumari, Rashmi, Anand, Atul, Kumar, Santosh, Sinha, B.P., 2017. Implants in glaucoma-an overview. IOSR Journal of Dental and Medical Sciences 16, 23–28. https://doi.org/10.9790/0853-1605052328. Schnaudigel, O.E., 1990. Anatomy of the ciliary sulcus. Fortschritte der Ophthalmologie: Zeitschrift der DeutschenOphthalmologischenGesellschaft 87 (4), 388–389. Schoenberg, E.D., Blake, D.A., Swann, F.B., Parlin, A.W., Zurakowski, D., Margo, C.E., Ponnusamy, T., John, V.T., Ayyala, R.S., 2015. Effect of two novel sustained-release drug delivery systems on bleb fibrosis: an in vivo glaucoma drainage device study in a
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Review
Implantable drainage devices in glaucoma: Quo vadis? ⁎
T
Khushwant S. Yadav , Sushmita Sharma Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed to be University, Mumbai, Maharashtra, India
A R T I C LE I N FO
A B S T R A C T
Keywords: Glaucoma Intraocular pressure Implantable drainage devices Ahmed glaucoma valve Valved Non-valved
Glaucoma, a gradually progressive class of either chronic eye disease or disorder, occurs due to increasing intraocular pressure. To reduce glaucoma, it is essential to stop the progression of IOP in the eye which is achieved by medical treatment, laser treatment and surgery. Profuse conventional drugs and laser surgeries are the primary go-tos for decreasing IOP. However, presently available marketed formulations using anti-glaucoma drugs have issues of either difficulty in crossing the blood retinal barrier (BRB) or lower systemic bioavailability. Hence, the drugs having lower therapeutic index would need to be administered frequently. This repeated systemic administration of high doses of drugs eventually leads to side effects, damage to the eye as well as patient noncompliance. Implants are deemed to be the suitable treatment left when such side effects are to be avoided. An eye implant is one of the choices for restoring the volume of the eye socket following evisceration and enucleation. Implantable drainage devices (IDD) aka glaucoma drainage devices (GDDs) or aqueous shunts are small reconstructive surgery devices, either solid or made of a tube fixed to an endplate. The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage opening and positioning the device properly on it. All implants are made with an objective of decreasing IOP by enhancing the fluid outflow from the eye. A critical comparison is made among different implants like Molteno: single-plate and Double-plate, Baerveldt drainage implant, Schocket implant, Ex-Press R50 implant, Ahmed glaucoma valve, Krypton implant to the latest one's including iStent, iStent inject, Hydrus, CyPass, XEN and InnFocus.
1. Introduction Glaucoma, a gradually progressive class of either chronic eye disease or disorder, occurs due to increasing intra-ocular pressure (IOP). IOP is well defined as the pressure created inside the eye which lies in the range of 10–21 mm Hg (Yan, 2011). The increased IOP, of more than 22 mm Hg is intolerant by normal eyes and ultimately the root of optic nerve injury. This continuous long term harm to optic nerve triggers failing of communication between retina and the brain leading finally to irreversible vision loss (Hertzog et al., 1996). The various factors affecting treatment of glaucoma are its causes, severity and susceptibility of patient (Gaasterland, 2004). Glaucoma is commonly associated with ocular hypertension. However, glaucoma can also occur when the intraocular pressure is normal, termed normal tension glaucoma. To reduce glaucoma, it is essential to stop the progression of IOP in the eye which is achieved by medical treatment, laser treatment and surgery (Yadav et al., 2019) Profuse conventional drugs and laser surgeries are the primary go-tos for decreasing IOP. Despite that some patients do not respond well to conventional eye drops because the medication gets absorbed on the surface layer of the eye into ⁎
conjunctiva blood vessels. In case of systemic absorption of drugs, it is necessary for the administered drug to cross BRB to arrive at posterior ocular tissue, while, to arrive at anterior tissue of the eye, it is required to cross blood aqueous barrier. Thus, these barriers are responsible for decreasing the intra-vitreal levels of lipid drugs which are poorly soluble by 10% to that of serum levels (Ghate and Edelhauser, 2006). Treatment with conventional drugs, on the other hand, has to be repeatedly administered in the target site which is eye due to their low therapeutic index which is essential to attain the desired therapeutic concentration of the drug (Nisha and Deepak, 2012). Drugs that are administered topically reaches the anterior chamber after it gets absorbed in the cornea body (Agrahari et al., 2016). The drug further reaches uvea by the aqueous flow movement and diffusion mechanism in the blood. The drug undergoes permeation via corneal epithelium by aqueous flow movement and the drug also gets absorbed via diffusion mechanism through the cornea. It is then transferred into the anterior chamber. The drug gets transported by aqueous flow and by diffusion into the blood circulation through anterior uvea. Drug molecules can permeate through the corneal epithelium by two pathways namely transcellular pathway for transportation of lipophilic drugs and
Corresponding author. E-mail addresses: [email protected], [email protected] (K.S. Yadav).
https://doi.org/10.1016/j.ejps.2019.03.007 Received 15 December 2018; Received in revised form 28 February 2019; Accepted 10 March 2019 Available online 12 March 2019 0928-0987/ © 2019 Elsevier B.V. All rights reserved.
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opening the fistula with the aid of silicon tube for draining of aqueous humor and also to curb conjunctival scarring by using endplate that maintains the potential space. Furthermore, it can bypass the BRB and also deliver onsite action. Overcoming BRB is possible because of intravitreal administration of drugs (Cholkar et al., 2013).
paracellular pathway for transporting hydrophilic drugs. The lipophilic drugs either rest in epithelial cells or progressively gets released into corneal stroma and anterior chamber. The lipophilic corneal epithelium is thus the barrier for drugs that are hydrophilic in nature. The drug finally arrives at aqueous humor and gets distributed in the iris and ciliary body (Agrahari et al., 2016). Glaucoma filtration surgery (GFS) procedure often escorts bleb formation which performs like reservoir and is analogous to other complications like bleb leakage and other infections caused as a result of formation of bleb (Chen et al., 1997, Joshi et al., 2005). Trabeculectomy, a surgical procedure is also associated with postoperative fibrosis as well as unrestricted scar formation in limbal area leading to its debacle and making implants as the tailor made surgical procedure (Broadway et al., 1998). Should one exhaust all of these methods, implants are deemed the suitable treatment left for glaucoma as they are designed to outdo the hurdles of GFS (Gedde et al., 2007). In this context the present minireview is aimed at presenting the advantages, applications and advances in the implantable drainage devices. A clear comparison between the presently available devices and cutting-edge technology in this field is presented in brief.
3. History of IDD: quo coepi? Earlier in the year 1906, Rollet and Moreau, carried out an experiment to treat absolute glaucoma where horse hair was positioned through corneal double paracentesis for removing the fluid or any gas and to drain the inflammatory cells of anterior chamber of eye. Then in the year 1912, first translimbal GDD, outlined by Zorab came into existence where silk thread was brought into play to drain the aqueous humor in the subconjunctival space (Lim et al., 1998). In 1959, Epstein introduced concept of inserting polyethene tube. Following, in the year 1969 MacDonald and Pearce made an implant by inserting silicon tube. Fig. 2 gives a pictorial presentation of major changes from 1960s to 2010 in the progress of implantable drainage devices. Subsequently, Molteno, in the year 1969 came with an idea of developing first non valved GDD which consisted of a tube devoid of a valve. Except profuse care and handling of the tube by suturing, shortfall of IOP surpasses resulting in hypotony. Hypotony is a term used in reference for IOP of 5 mm Hg and further eye collapsing. To overcome the hassle, economically and socially advanced valve came into light. Initiated and put forward in at the later year in 1976, Krupin introduced first valved GDD with characteristics preventing hypotony. Thereafter, in 1993, the model was improvised when Ahmed glaucoma valve (AGV) was introduced, designed in various shapes and sizes and in a way that the valve opened with IOP value of 8–12 mm Hg. These devices are growing over recent years and led to development of ExPress R50 (Fig. 3) along with Istent, InnFocus and AqueSys (Acosta et al., 2006; Al-Shohani, 2017).
2. Implantable drainage devices Implantable drainage devices (IDD) are small reconstructive surgery devices which create an alternate pathway for the outflow of aqueous humor in the eye. These implants are usually adapted to when there is a need for restoring the volume of the eye socket following evisceration (a cosmetic procedure where extraocular muscles and white fibrous portion of the eye called sclera are unharmed) and enucleation (a procedure involving removal of the whole eyeball (Kitzmann et al., 2003). The IDD is also known as a glaucoma drainage device (GDD) or as aqueous shunt (Glaucoma Research Foundation, 2018). Fig. 1 is a schematic representation of implantable drainage device. These devices are a solid body made up of a tube of silicone of approximate diameter of size 300 μm, fixed to an endplate of polypropylene. The one side of the tube is fixed to anterior region while the other side usually serves attachment to the plate in subconjunctival region of the eye (Saha et al., 2017). IDD work by opening the fistula with the aid of silicon tube for draining of aqueous humor and also to curb conjunctival scarring by using endplate that maintains the potential space (Ekinci et al., 2014). There are various conditions which puts implants as the favorable choice, one among them being able to bypass BRB and delivering onsite action of the administered drug. Secondly, it maintains the drug release over prolonged period. Also, in case of systemic administration, it provides minimum side-effects (Silva et al., 2010). IDD work by
4. Materials used in construction of implants IDD currently in use are solid spheres with thin body and desired length (Bene et al., 2008) made of different materials akin to penetrable polyethylene or coralloid hydroxyapatite (Baino and Potestio, 2016). Earlier, they were made of materials like glass, silk thread, acrylic, collagen, platinum, teflon, autologous lacrimal canaliculus and cartilage (Iosrjournals.org., 2018) which showed high complication rates like formation of scar near the limbus, excessive migration and erosion of conjunctiva. IDD are drug delivery systems which can be made either from degradable or non-degradable materials. The biodegradable materials include biodegradable polymers while non-biodegradable materials comprise endplates made of stainless steel, metals and non-biodegradable polymers. Biodegradable polymers are polylactide-co-glycolide acid (PLGA) (Yadav et al., 2011), silicon and polylactic acid (PLA). These biodegradable polymers are degraded (get absorbed) and do not leave any remains of the drug carrier, thereby eliminating the need for surgical removal unlike with non-biodegradable polymers where the carriers may, sometimes, accumulate and lead to many complications like cataract, hemorrhage etc. The examples of implants made off biodegradable polymers include Retisert® and IIuvien® (Del Amo and Urtti, 2008). Non-biodegradable polymers provide better prolonged release but require surgical removal of the polymers as they do no degrade inside the body. Some of the non-biodegradable polymers are polyvinyl alcohol, ethylene vinyl alcohol, etc. The examples of such type of implant include Ozurdex® and Surodex® (Haghjou et al., 2011).
Fig. 1. Schematic representation of implantable drainage device. An IDD consists of a solid body and a tube. The body is made of a tube of silicone of approximate diameter of size 300 μm which is fixed to an endplate usually made of polypropylene. (Abbreviations: IDD - implantable drainage device).
5. Mechanism of action of the implants The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage 2
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Fig. 2. History of implantable drainage devices. In the year 1969, first non valved IDD was developed which consisted of a tube devoid of a valve. Then in 1970s, single plate was introduced for better drainage but then led to side effects like aphakia. Later in 1980s double plate was introduced with improved intraocular pressure but had a complication of hypotony. Thereafter, Molteno Pressure Ridge implant emerged, followed by Molteno3 in 2000s and Molteno3s in 2010. (Abbreviations: IDD - implantable drainage device).
tolerated biomaterial, is inserted either in anterior chamber or in between the base of the iris and ciliary body called ciliary sulcus (Schnaudigel, 1990). It can also be placed in pars plana, present in uvea, portion of ciliary body. The plate is positioned on sclera typically in superior temporal quadrant. Tube serves the function of draining the fluid in the posterior region of implant (Wang and Barton, 2017). The tube allows flowing of fluid to plate placed on upper eyelid surface and thus acts as an artificial drain. The fluid is then passed through this and gets reabsorbed into the body fluids (Matthew Emanuel, 2018; Haffner et al., 2017). Nevertheless, solid sphere implantation is laborious as the sclera cavity should be wide enough to fit the sphere. An alternative method is favorable where liquefied implants can be injected by making a small incision (Yeatts et al., 2002). Implants may pose a threat of causing unwarranted injury to the eye and thereby proper handling of implant is necessary. Refusing to acknowledge the risks of surgeries, intraocular implants are outlined with a goal of producing sustained release from the polymeric material. The implant serves the advantages of bypassing the blood-retinal barrier and delivering onsite action. Very less quantity of drug is required for implantation (Bourges et al., 2006). Implants are used for managing refractory glaucoma, complicated glaucomas following keratoplasty, glaucoma succeeding injury or any trauma in the eye. Moreover, it is useful for treating congenital glaucoma, primary open angle glaucoma (POAG), neovascular glaucoma, (Sidoti et al., 1995) uveitic glaucoma (UG) (Da Mata et al., 1999) and other glaucomas where conventional treatment fails to cope.
Fig. 3. Ex-PRESS Mini glaucoma shunt. The Ex-PRESS glaucoma shunt, made of stainless steel consists of a spur and a flat backplate. The spur is designed to prevent extrusion while external backplate serves the function of preventing intrusion. The device constitutes a relief port which offers alternative pathway for outflow of aqueous humor.
6. Pathophysiology at the site of implant Fig. 4. Mechanism of action of implantable drainage devices. The figure illustrates the implantation of the ocular drainage device and its valve mechanism. The drainage tube allows the outflow of aqueous humor. The aqueous humor is drained in the body of the plate, positioned in the subconjunctival space. Valve mechanism of the device consists of elastic membranes made of silicone. These membranes are designed in such a way that in response to fluctuations in intraocular pressure, the valves open and close. As IOP extends its threshold value, the aim is to decrease the IOP Pressure difference is created because of the wider cross section of the inlet than outlet which allows opening of the valve. Reduced hypotony is observed with the decreased pressure and tension created in the silicone membrane. (Abbreviations: IOP - intraocular pressure)
When implant is positioned, fibrous capsule keeps developing over several weeks around the end plate. There is no fibroblast adhesion on the silicone material thus making IDD an important feature for its success. The aqueous humor flows from the ciliary body present in the anterior region of the eye and passes through fibrous capsule following end plate (Saha et al., 2017). It flows by the mechanism of passive diffusion to finally be flown by the lymphatic drainage system. The fibrous capsule thus serves as the important site for obstructing the aqueous humor outflow (Fig. 6). Henceforth, performance of drainage surgery is totally dependent on the breadth of the fibrous capsule and area of encapsulation. The implant surface area is an imperative factor for the long term IOP control with all the devices, as it determines the tissue response, bleb size and fibrous capsule thickness that control the pathway of aqueous via bleb wall (Glaucoma drainage devices).
opening and positioning the device properly on it. Glaucoma can be reduced mainly via two mechanisms, either by elevating the outflow of aqueous fluid or by decreasing its formation (Fig. 4). All implants are made with an objective of decreasing IOP by enhancing the aqueous fluid outflow from the eye. In standard surgery procedures, GFS, like trabeculectomy or sclerostomy, a minute drainage hole is created in the sclera (Karmel, 2004). This hole allows the fluid to drain in the delicate covering of the eye, conjunctiva. Considering implant surgery, the device requires positioning in the upper or lower eyelid, preferably cornea-sclera cavity (Ozqur et al., 2005) or under the conjunctiva. Irrespective of the type of implant, a tube of silicone, a well-
7. Types of implants and their advances There are two types of distinguishing implants, valved and non valved implants. Non valved also called non-restrictive implants are IDDs which consist of a tube made of silicon and is joined to an endplate. The endplate represents a surface for the formation of bleb. Non valved implants should be blocked for short term to prevent hypotony 3
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prior to development of adequate fibrosis near the plate. In order to prevent hypotony, valved devices play a productive role as they instantly allow the flow after implantation (Brandt et al., 2018). Non-valved implants can be further divided as Single-plate Molteno (SPM), Double-plate Molteno (DPM), Baerveldt drainage implant (BDI), Schocket implant, Ex-Press R50 implant. Single-plate Molteno is the implant in which a silicone tube is fixed to 135 mm2 endplate made of polypropylene. Double-plate Molteno (DPM) is similar to that of a single plate Molteno except the fact that there is a second end plate fixed to either right side or left side of the existing initial endplate. Thus, the surface area is twice the single-plate Molteno. The size of the silicone tube is 10 mm (Schwartz et al., 2006). The BDI when compared to DPM has benefit of easy insertion as it requires one quadrant for dissection. As well, the silicon plate, less inflammatory and more bendable than polypropylene 6 owes easy handling and more flexibility in the quadrant. However, BDI has disadvantages like heterotropia, diplopia and motility restriction, because of large implant size (Smith et al., 1993). BDI consists of a pliable, soft silicone endplate with sizes 250 mm2, 350 mm2 and also 500 mm2 impregnated with barium fixed to silicone tube (Schwartz et al., 2006). Baerveldt posed a slight risk of emptying the anterior chamber (Smith et al., 1993). Schocket implant is a tube made of silicone where its one end is joined to the anterior chamber while the other is tied beneath retinal encircling band. Ex-Press R50, an implant made of stainless steel is 2–3 mm long and has 0.4 mm diameter tube, which helps in attachment of the anterior chamber and intrascleral space. Initially, it was inserted under the conjunctiva but currently they are placed under the sclera in order to avoid further filtrations (Fig. 5). (Huerva et al., 2016; Bissig et al., 2010; De Feo et al., 2009). Valved, also called restrictive implants comprises of AGV, where the end plate is scarab shaped and is formed of either silicone or polypropylene. The silicone tube is joined to the body of propylene. The valve is made in a way that it opens when IOP measures 8 mm Hg. AGV in analogy with BDI showed higher hypertension rate. Also, increase in IOP was observed after 1–2 month of implantation. In regards to bleb formation, AGV had more effect than BDI. However, for hypotony and choroidal shedding, BDI raised the complications following ligature (Syed et al., 2004). Krupin slit valve (KSV) is another type of valved implants where the silicone tube is attached to oval silastic endplate. The endplate has a surface area of 180 mm2. There are some GDDs with varying resistance such as Molteno dual ridge (MDR) and Baerveldt bioseal implant. The plate's top is divided into two separate spaces in the molten dual
ridge device in order to limit the initial drainage area. Aqueous escapes into the narrow channel that separates these two concentric ridges, but it also has to overcome the resistance from conjunctival tissue apposition in order to flow further. This is achieved later by partially encapsulating the plate element which results in the overlying tissue clearing off of the inner pressure ridge, allowing an unrestricted aqueous flow into the overlying space. In the modified Baerveldt implant, the ‘Bioseal’ element is opposed to the sclera having absorbable sutures to secure early flow resistance, prohibiting initial aqueous to escape from beneath. The common problem with both the approaches is, much like trabeculectomy, the poor tissue apposition. There is varying early flow resistance and unpredictable initial IOP levels (Kim et al., 2016). MDR implant obstructs the drainage area. The top region of the plate is separated into two portions with the help of a V-shaped ridge. Baerveldt device consists of an endplate of silicone impregnated with barium with a surface area of 250 mm2 or 350 mm2 (Singh et al., 2013; Schwartz et al., 2006) (Table 1). 8. Advances and developments in implants: quo nunc? Traditional surgery, in defiance of its efficacy, leads to side effects such as hypotony, endophthalmitis, hemorrhage, surface thinning and scarring, implant exposure, infection of implant (Zhang et al., 2015), eye surface diseases and socket syndrome (Vagefi et al., 2011). To overcome the side effects while maintaining efficacy, current targets are to secure the Minimally Invasive Glaucoma (MIGS) procedures. These procedures are found to be more effective than traditional method of surgery as it gives importance to patient safety. In addition, they are more effective in reducing IOP (Ansari, 2017). While giving a look through published articles, it was found that most of the implants are yet to be approved. The reason contributing to this statement is ‘lack of knowledge’ for differentiating types of implants. Also, there is a lack of randomized clinical trials which is essential to evaluate the long term complications and efficacies of different implants. MIGS implants can then come into account and serve better. Considering, the type of flow, they are classified into three main implants, first are the implants that enhance trabecular outflow through trabecular meshwork implants. Second one increases the uveoscleral outflow through suprachoroidal route by developing a drainage path in the sub-conjunctival region and third type of implants creates subconjuctival drainage pathway. These are summarized in the Table 2 (Ansari, 2017). 9. Pre-clinical studies on IDDs The potency and correlation of non-valved implants with that of two valved implants so to treat recalcitrant glaucoma was well executed by Taglia et al. (2002) where the study compared DPM with KSV and AGV. The reports concluded that DPM implantation maintained the IOP in the range of 5–15 mm Hg when compared to AGV. The success rates were 80% for DPM implanted patients at the end of a year followed by KSV with 39% and lastly AGV with 35% success rate. Howbeit, the study summed up that the complications were least for AGV patients. The efficacy of intracameral implantation in rabbits for long term therapy of glaucoma was well understood by Kim et al. (2016) where an implant of polycaprolactone loaded with selective EP2 agonist DE-117 was developed. The single device for drug delivery offered outcomes like significant reduction in IOP in rabbits for around 23 weeks. Also, it maintained the concentration of the drug DE-117 in the target tissue until 6 months at the rate of 0.5 μg/day and thus circumvented patient compliance. Evan et al. came with a concept of creating sustained duo drug delivery systems with a combination of non-biodegradable system and biodegradable system. Poly(2-hydroxyethyl methacrylate) [P (HEMA)] with MMC as non-biodegradable polymer while PLGA with 5fluorouracil (5-FU) as biodegradable polymer constituting MMC or devoid of MMC were used for the same. The study focused to report the
Fig. 5. Conjunctiva under normal operation and encapsulation. The drainage implant cross section focuses on the development of the fibrous capsule tissue, bleb, with time. The bleb acts as a pool for aqueous humor. Under normal condition, the IOP is under control and there is reduced bleb thickness whereas in some cases there is formation of dense layered collagen as depicted on the right side in the figure. Fibrous encapsulated bleb (dense layer of collagen) shows higher IOP because of the reduced capacity of the device to drain aqueous humor. (Abbreviations: IOP - intraocular pressure). 4
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Table 1 Classification of intraocular implants for treating glaucoma (Al-Shohani, 2017). Implants
Valved/non-valved
Description
Size
Single-plate Molteno Double-plate Molteno Baerveldt drainage implant
Non-valved Non-valved Non-valved
Silicone tube + single polypropylene endplate Silicone tube + double polypropylene endplate Silicone tube + silicone impregnated with barium endplate
Schocket implant Ex-Press R50 implant Ahmed glaucoma valve Krupin-slit valve
Non-valved Non-valved Valved Valved
Silicone tube Tube of stainless steel, no end plate Silicone tube + polypropylene endplate Silicone tube + silicone endplate
340 μm-inner diameter of tube, 135 mm2-endplate 340 μm-inner diameter of tube, 268 mm2-endplate 300 μm-inner diameter of tube, 250 mm2, 350 mm2 and 500 mm2-endplates. Width 4 mm and 6 mm, diameter- 24 mm 2–3 mm long, 0.4 mm diameter tube 300 μm-inner diameter of tube, 185 mm2-endplate 300 μm-inner diameter of tube, 180 mm2-endplate
Table 2 An insight on implants approved by US FDA. Implant types based on flow
Implant
Materials
Dimensions
Examples
US FDA approval status
Trabecular
iStent
Coated with heparin
1 mm × 0.3 mm
iStent inject
Non-ferromagnetic, made of titanium Alloy of nickel and titanium Nitinol Polymers of amide
230 μm × 360 μm
Glaukos Corp. (USA) Glaukos Corp. (USA) Ivantis Inc. (USA) Alcon (USA)
Approved in June 2012 (Investors.glaukos.com, 2019). Approved in June 2018 (Fda.gov, 2019a, 2019b) Approved in August 2018 (Fda.gov, 2019a, 2019b). Approved in July 2016 (Medscape., 2019). Approved in November 2016 (Glaucoma Research Foundation, 2019).
Hydrus Uveo-scleral
CyPass
Subconjunctival ab interno
XEN
Gelatin in crosslinkage with glutaraldehyde
8 mm in length 6.35 mm in length, external diameter510 μm, 300 μm-internal diameter 6 mm in length, 45 μm–internal diameter
Allergen (Ireland)
Fig. 7. Part of plant body in action under applied magnetic field. Magneto elastic actuators are linked to IDDs as they can control cellular adhesion on the surface of the body of implant. These actuators are fixed within the IDD or attached to it prior to the surgery. The stresses produced via vibration of the actuator reduce adhesion of fibrous tissue and also obstructs encapsulation. Thus, it aids in proper management of IOP because of easy outflow of aqueous humor. The actuator constitutes paddles and spring. The vibrations occur in the paddle and causes drainage of aqueous humor. The springs are attached to the anchor. (Abbreviations: IDD - implantable drainage device, IOP - intraocular pressure).
Fig. 6. Drainage tube with micro actuators. Implantable drainage device along with microactuators, vibrates on exposure to magnetic field.
effect of MMC as fibrosis (thickening of connective tissue as a consequence of injury) reducing agent when connected to AGV in albino rabbit model were 48 rabbits were taken and then divided into equal groups of 6 based on polymers. It was observed that thickness of the bleb wall was significantly decreased in systems with combo of nonbiodegradable and biodegradable polymers. Evan et al. accomplished his desired aim and proved it successfully when the system displayed reduced fibrosis and no harmful effects (Schoenberg et al., 2015).
Sheybani et al. revealed the IOP reduction from 23 mm Hg initially to IOP of 14 mm Hg at the end of year. The mean IOP reduction was found to be 36.4%, slightly higher than the above case. Also, XEN 45 attained a steady-state pressure at 7.56 mm Hg at the rate of 2.5 μL/min (Sheybani et al., 2015). In another research, Moore et al. (2015) scrutinized the aftermath of placing sustained release fluocinolone acetonide drainage implant (Retisert) approved by United States Food and Drug Administration (FDA) in the year 2005, in combination with an AGV in eyes of patients suffering from UG and placing AGV alone in patient's eyes suffering from either POAG or UG. The surgery was said to accomplish the desired goal only when IOP was in the range of 5–18 mm Hg. The duration for mean IOP reduction was higher in Retisert eyes of patients suffering from UG than patients suffering from POAG. Ultimately, Moore et al.
10. Clinical studies on IDDs Galal et al. (2017) evaluated XEN, Aquesys, gelmicrostents to know its effectiveness in treating POAG. In the following procedure, there was decline in IOP from 10 to 24 mm Hg to 2–20 mm Hg in first week. And finally by the end of a year, the IOP dropped to 6–18 mm Hg. However, there was a complication of choroidal detachment observed. The evaluation concluded that XEN implant is very effective in significantly reducing IOP for a period of 1-year minimum follow up and thus treating POAG. A similar study was performed which aimed at describing fluidics of non valved glaucoma and IOP reduction. Studies of 5
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Acknowledgement
interpreted that Retisert in combination with AGV implantation had greater impact on duration of action than AGV alone in the eyes of patients with UG or POAG.
The authors are thankful to Mr. Viral Bakhai and Ms. Shweta Sharma for their valuable help in drawing and editing the figures.
11. IDD: where are these devices going (quo vadis)? References 11.1. Regulatory status Acosta, A.C., Espana, E.M., Yamamoto, H., Davis, S., Pinchuk, L., Weber, B.A., Orozco, M., Dubovy, S., Fantes, F., Parel, J.M., 2006. A newly designed glaucoma drainage implant made of poly (styrene-b-isobutylene-b-styrene): biocompatibility and function in normal rabbit eyes. Arch. Ophthalmol. 124 (12), 1742–1749. Agrahari, V., Mandal, A., Agrahari, V., Trinh, H.M., Joseph, M., Ray, A., Hadji, H., Mitra, R., Pal, D., Mitra, A.K., 2016. A comprehensive insight on ocular pharmacokinetics. Drug delivery and translational research 6 (6), 735–754. Al-Shohani, A.D.H., 2017. Hydrogel Formulations for Ophthalmic Delivery. Doctoral dissertation. UCL (University College London). Ansari, E., 2017. An update on implants for minimally invasive glaucoma surgery (MIGS). Ophthalmol Therapy 6 (2), 233–241. Baino, F., Potestio, I., 2016. Orbital implants: state-of-the-art review with emphasis on biomaterials and recent advances. Mater SciEng C Mater Biol Appl. 69, 1410–1428 Dec 1. (pmid: 27612842). Bene, E.A., Morrill, T.J., Mulhern, M.B., Wandel, T.L., Taylor, J.B. and Mir, L., Becton Dickinson and Co, 2008. Ocular implant and methods for making and using same. U. S. Patent Application 12/050,346. Bissig, A., Feusier, M., Mermoud, A., Roy, S., 2010. Deep sclerectomy with the ex-PRESS X-200 implant for the surgical treatment of glaucoma. Int. Ophthalmol. 30 (6), 661–668. Bourges, J.L., et al., 2006. Intraocular implants for extended drug delivery: therapeutic applications. Adv. Drug Deliv. Rev. 58, 1182–1202. Brandt, J.D., Hammel, N., Fenerty, C., Karaconji, T., 2018. Glaucoma drainage devices. In: Grajewski, A., Bitrian, E., Papadopoulos, M., Freedman, S. (Eds.), Surgical Management of Childhood Glaucoma. Springer, Cham. Broadway, D.C., Grierson, I., Hitchings, R.A., 1998. Local effects of previous conjunctival incisional surgery and the subsequent outcome of filtration surgery. Am J. Ophthalmol. 125 (6), 805–818. Chen, P.P., Yamamoto, T., Sawada, A., Parrish II, R.K., Kitazawa, Y., 1997. Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese Glaucoma societies. J. Glaucoma 6 (3), 192–196. Cholkar, K., Patel, S.P., Vadlapudi, A.D., Mitra, A.K., 2013. Novel strategies for anterior segment ocular drug delivery. J. Ocul. Pharmacol. Ther. 29 (2), 106–123. Da Mata, A., Burk, S.E., Netland, P.A., Baltatzis, S., Christen, W., Foster, C.S., 1999. Management of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology 106, 2168–2172. De Feo, F., Bagnis, A., Bricola, G., Scotto, R., Traverso, C.E., 2009. Efficacy and safety of a steel drainage device implanted under a scleral flap. Canadian Journal of Ophthalmology/Journal Canadiend'Ophtalmologie 44 (4), 457–462. Del Amo, E.M., Urtti, A., 2008. Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov. Today 13 (3–4), 135–143. Ekinci, M., Çagatay, H.H., Ceylan, E., Keles, S., Koban, Y., Gokce, G., Huseyinoğlu, U., Ozcan, E., Oba, M.E., 2014. Reduction of conjunctival fibrosis after trabeculectomy using topical α-lipoic acid in rabbit eyes. J. Glaucoma 23 (6), 372. Fda.gov, 2018. [online] Available at. https://www.fda.gov/downloads/MedicalDevices/ NewsEvents/WorkshopsConferences/UCM390340.pdf, Accessed date: November 2019. Fda.gov, 2019a. Hydrus® Microstent - P170034. [online] Available at. https://www.fda. gov/MedicalDevices/ProductsandMedicalProcedures/ DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm620440.htm. Fda.gov, 2019b. iStent Inject Trabecular Micro-Bypass System (Model G2-M-IS) – P170043. [online] Available at. https://www.fda.gov/medicaldevices/ productsandmedicalprocedures/deviceapprovalsandclearances/recentlyapproveddevices/ucm612792.htm. Gaasterland, D.E., 2004. Advanced glaucoma. In: Higginbotham, E.J., Lee, D.A. (Eds.), Clinical Guide to Glaucoma management. Butterworth Heinemann, Woburn, MA, pp. 171–182. Galal, A., Bilgic, A., Eltanamly, R., Osman, A., 2017. XEN glaucoma implant with mitomycin C 1-year follow-up: result and complications. J. Ophthalmol. 2017. Gedde, S.J., Schiffman, J.C., Feuer, W.J., Herndon, L.W., Brandt, J.D., Budenz, D.L., Tube Versus Trabeculectomy Study Group, 2007. Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J. Ophthalmol. 143 (1), 9–22. Ghate, D., Edelhauser, H.F., 2006. Ocular drug delivery. Expert opinion on drug delivery 3 (2), 275–287. Glaucoma Research Foundation, 2018. Glaucoma Implant Surgery. [online] Available at. https://www.glaucoma.org/treatment/glaucoma-implants.php, Accessed date: October 2019. Glaucoma Research Foundation, 2019. Allergan receives FDA approval for XEN Glaucoma Treatment System. [online] Available at. https://www.glaucoma.org/news/ allergan-receives-fda-approval-for-new-xen-glaucoma-treatment-system.php. Haffner, D.S., Cogger, J.J., Kalina, C.R. and Crimaldi, D.D., Glaukos Corp, 2017. System and method for delivering multiple ocular implants. U.S. Patent 9,554,940.) Haghjou, N., Soheilian, M., Abdekhodaie, M.J., 2011. Sustained release intraocular drug delivery devices for treatment of uveitis. J. Ophthalmic Vis. Res. 6 (4), 317–329. Hertzog, L.H., Albrecht, K.G., LaBree, L., Lee, P.P., 1996. Glaucoma care and conformance with preferred practice patterns: examination of the private, community-based ophthalmologist. Ophthalmology 103 (7), 1009–1013.
The FDA has grouped medical devices mainly into 3 classes, namely, class I, II and class III. A class III device is elaborated as devices which supports or comforts human life and is of prime importance in mitigating diseases and henceforth is epitome of highest regulation. The safety and efficacy of these devices are maintained in application called premarket approval. GDD's are classified under class III where FDA acquires 51O(k) application. The implantable devices which are currently approved are GlaukosiStent and AGI GDD. Many of GDD's are under investigation which requires premarket approval under the category of safety and also to meet the demands of effectiveness (Fda.gov., 2018). 11.2. Recent landmarks achieved The IDD has waffling degrees of success because of accumulation of microorganism on the device either during or after implantation, more precisely termed biofouling. Therefore, the latest IDD, created by Hyowon Lee, aimed to treat glaucoma and have grown reputation as it combats the biofouling by using concept of advanced microtechnology. The IDD has ability to clear itself from adverse bio buildup. The drainage tube is made of magnetic nickel microactuators which on exposure to magnetic field vibrate (Fig. 6, 7). These vibrations flush out the fluid along with the biomaterials built up in the tube (Service, 2019). 11.3. Concluding remarks IDD's have been popular in decreasing the IOP in eyes for patients with failed GFS. IDD's and their clinical trials have taken a great leap in the field of glaucoma over the years and these advances will set objectives for future. Until now, numerous adjustments have been made in the design, size and material of the implant as per patient's comfort. Many factors are responsible in throwing light upon this area with the involvement of technologies like advance sensors, micro technology and use of micro actuators. The field of science is looking forward to the implication of IDD in coming years for innovation and advance inventions in clinical management leading to the betterment of glaucoma patients. At present, IDD's is a part of clinical trials which focuses on forming a thinner capsule with outstanding hydraulic conductivity. It stands on the rationale of changing the design of the frequently used implantable drainage devices from a common plate design to a cylindrical form for achieving marked down tension on the fibrous capsule. The IDD's are newly designed with an objective of producing minimal side effects and more foreseeable control over IOP. The premonition behind implants is augmenting standard glaucoma surgery which successfully is attained by surgically creating a drainage opening and positioning the device properly on it. Safety and efficacy parameters with respect to adverse effect management have been taken care of from the initiation of implants by emphasizing on the prevention of adverse events. Although, some rare and uncommon complications like bleeding inside the eye, fluid building inside the retina, eye infection may result. Tube related complications occur if not placed properly and cause swelling of cornea. Most of the side effects set right with time yet unfortunately glaucoma is irreversible blindness. Wherefore, the reason for implanting the device is for a preventive cause. Careful implanting of device is therefore required to minimize the postoperative complications. 6
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rabbit model. Translational vision science & technology 4 (3), 4. Schwartz, K.S., Lee, R.K., Gedde, S.J., 2006. Glaucoma drainage implants: a critical comparison of types. Curr. Opin. Ophthalmol. 17 (2), 181–189. Service, P, 2019. Purdue's giant leap toward personalized medicine helps eyes drain themselves for glaucoma patients. [online] Purdue.edu. Available at. https://www. purdue.edu/newsroom/releases/2018/Q4/purdues-giant-leap-toward-personalizedmedicine-helps-eyes-drain-themselves-for-glaucoma-patients.html. Sheybani, A., Reitsamer, H., Ahmed, I.I.K., 2015. Fluid dynamics of a novel micro-fistula implant for the surgical treatment of glaucoma. Invest. Ophthalmol. Vis. Sci. 56 (8), 4789–4795. Sidoti, P.A., Dunphy, T.R., Baerveldt, G., LaBree, L., Minckler, D.S., Lee, P.P., et al., 1995. Experience with the Baerveldt glaucoma implant in treating neovascular glaucoma. Ophthalmology 102, 1107–1118. Silva, G.R.D., Fialho, S.L., Siqueira, R.C., Jorge, R., Júnior, C., da Silva, A., 2010. Implants as drug delivery devices for the treatment of eye diseases. Brazilian Journal of Pharmaceutical Sciences 46 (3), 585–595. Singh, P., Kuldeep, K., Tyagi, M., Sharma, P.D., Kumar, Y., 2013. Glaucoma drainage devices. Journal of Clinical Ophthalmology and Research 1 (2), 77. Smith, S.L., Starita, R.J., Fellman, R.L., Lynn, J.R., 1993. Early clinical experience with the Baerveldt 350-mm2 glaucoma implant and associated extraocular muscle imbalance. Ophthalmology 100, 914–918. Syed, H.M., Law, S.K., Nam, S.H., et al., 2004. Baerveldt-350 implant versus Ahmed valve for refractory glaucoma: a case-controlled comparison. J. Glaucoma 13, 38–45. Taglia, D.P., Perkins, T.W., Gangnon, R., Heatley, G.A., Kaufman, P.L., 2002. Comparison of the Ahmed glaucoma valve, the Krupin eye valve with disk, and the double-plate Molteno implant. J. Glaucoma 11 (4), 347–353. Vagefi, M.R., McMullan, T.F., Burroughs, J.R., Georgescu, D., McCann, J.D., Anderson, R.L., 2011 Mar-Apr. Orbital augmentation with injectable calcium hydroxylapatite for correction of postenucleation/evisceration socket syndrome. OphthalPlastReconstr Surg 27 (2), 90–94 (pmid:20683373). Wang, J., Barton, K., 2017. Aqueous shunt implantation in glaucoma. Taiwan journal of ophthalmology 7 (3), 130. Yadav, K.S., Jacob, S., Sachdeva, G., Sawant, K.K., 2011. Intracellular delivery of etoposide loaded biodegradable nanoparticles: cytotoxicity and cellular uptake studies. J. Nanosci. Nanotechnol. 11 (8), 6657–6667. Yadav, K.S., Rajpurohit, R., Sharma, S., 2019. Glaucoma: current treatment and impact of advanced drug delivery systems. Life Sci. 221, 362–376. Yan, J., 2011. Conf. Proc. IEEE Eng. Med. Biol. Soc. Boston, MA. Yeatts, R.P., Grim, W., Stanton, C., Curry, C., 2002. Injectable hydroxyapatite paste as an option for ocular implantation after evisceration. Ophthalmology 109 (11), 2123–2128 Nov. (pmid:12414426). Zhang, Y., Zhang, M.N., Wang, X., Chen, X.F., 2015. Removal of the eye in a tertiary care center of China: a retrospective study on 573 cases in 20 years. Int J Ophthalmol. 8 (5), 1024–1030 Oct 18. (pmid:2655822).
Huerva, V., Soldevila, J., Ascaso, F.J., Lavilla, L., Muniesa, M.J., Sánchez, M.C., 2016. Evaluation of the Ex-PRESS® P-50 implant under scleral flap in combined cataract and glaucoma surgery. International journal of ophthalmology 9 (4), 546. Investors.glaukos.com, 2019. FDA approval of the istent trabecular micro-bypass. [online] Available at. http://investors.glaukos.com/investors/press-releases/pressrelease-details/2012/FDA-Approval-Of-The-iStent-Trabecular-MicroBypass/default. aspx. Iosrjournals.org, 2018. [online] Available at. http://iosrjournals.org/iosr-jdms/papers/ Vol16-issue5/Version-5/F1605052328.pdf, Accessed date: November 2019. Joshi, A.B., Parrish, R.K.I.I., Feuer, W.F., 2005. 2002 Survey of the American Glaucoma Society: practice preferences for glaucoma surgery and antifibrotic use. J. Glaucoma 14 (2), 172–174. Karmel, M., 2004. Filtering surgery takes a new direction: will it revolutionize the field? EyeNet 8, 33–36. Kim, J., Kudisch, M., Mudumba, S., Asada, H., Aya-Shibuya, E., Bhisitkul, R.B., Desai, T.A., 2016. Biocompatibility and pharmacokinetic analysis of an intracameral polycaprolactone drug delivery implant for glaucoma. Investig. Opthalmology Vis. Sci. 57, 4341–4346. Kitzmann, A.S., Weaver, A.L., Lohse, C.M., Buettner, H., Salomao, D.R., 2003. Clinicopathologic correlations in 646 consecutive surgical eye specimens, 1990–2000. Am J ClinPathol 119 (4), 594–601. Lim, K.S., Allan, B.D.S., Lloyd, A.W., Muir, A., Khaw, P.T., Lim, K.S., Allan, B.D.S., Lloyd, A.W., Muir, A., Khaw, P.T., 1998. Glaucoma drainage devices; past, present, and future. Br. J. Ophthalmol. 82 (9), 1083–1089. Matthew Emanuel, M., 2018. Glaucoma drainage implant surgery - Glaucoma Associates of Texas. online. Available at Glaucoma Associates of Texashttp:// glaucomaassociates.com/incisional-glaucoma-surgery/glaucoma-drainage-implantsurgery/, Accessed date: October 2019. Medscape, 2019. FDA updates advice on withdrawn CyPass glaucoma stent. [online] Available at. https://www.medscape.com/viewarticle/903990. Moore, D.B., Stinnett, S., Jaffe, G.J., Asrani, S., 2015. Improved surgical success of combined glaucoma tube shunt and Retisert® implantation in uveitic eyes: a retrospective study. Ophthalmol Therapy 4 (2), 103–113. Nisha, S., Deepak, K., 2012. An insight to ophthalmic drug delivery system. International Journal of Pharmaceutical Studies Research 3 (2), 9–13. Ozqur, O.R., Akcay, L., Doğan, O.K., 2005 Jan. Evisceration via superior temporal sclerotomy. Am J. Ophthalmol. 139 (1), 78–86 (pmid:15652831). Saha, Bhawesh, Kumari, Rashmi, Anand, Atul, Kumar, Santosh, Sinha, B.P., 2017. Implants in glaucoma-an overview. IOSR Journal of Dental and Medical Sciences 16, 23–28. https://doi.org/10.9790/0853-1605052328. Schnaudigel, O.E., 1990. Anatomy of the ciliary sulcus. Fortschritte der Ophthalmologie: Zeitschrift der DeutschenOphthalmologischenGesellschaft 87 (4), 388–389. Schoenberg, E.D., Blake, D.A., Swann, F.B., Parlin, A.W., Zurakowski, D., Margo, C.E., Ponnusamy, T., John, V.T., Ayyala, R.S., 2015. Effect of two novel sustained-release drug delivery systems on bleb fibrosis: an in vivo glaucoma drainage device study in a
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