Fig. 13.4  Refillable silicone episcleral implanted device used for injection of carmustine solutions (from Liu et al. 1979). Copyright 1979 Association for Research in Vision and Ophthalmology. Reproduced with permission of INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE in the format Other Book via Copyright Clearance Center

13.4  Ophthalmic Refillable Devices

13.4.1  Invasiveness and Refilling Frequency

To be successful for ophthalmic purposes, surgical implantation followed by subsequent repetitive refill procedures should accommodate both the patient’s and physician’s practices with respect to management of the specific disease. The factors include (a) the accepted re-visit interval of the patient to the ophthalmologist’s office, (b) the patient’s visual status, and (c) the speed of the disease progression. In the case of glaucoma treatment, it is common practice that patient follow-up visits are typically no less than every 3 months and often are at 4–6-month intervals. These match reasonable periods for a refill procedure. However, glaucoma patients whose intraocular pressure is easily controlled with drop medication and whose vision has not yet been dramatically impacted by the disease are unlikely to be willing candidates for surgical implantation of a refilling device. Rather, patients at later disease

stages or those having difficulty with eyedrop compliance have shown willingness to undergo various surgical steps including implantation of drainage valves or trabeculectomy to arrest further progression. Moreover, similar to medically controlled and compliant glaucoma patients, in a slow progressing disease state such as the dry form of age-related macular degeneration (AMD), where vision may be reasonably good, the patient will be more risk adverse and thus resistant to surgical procedures which have a high level of complexity or invasiveness. Furthermore, their desire for retreatment will gravitate toward at least a 6–12-month interval. In more rapidly progressing disease, such as the wet form of AMD, historical experience has shown that patients have been willing to accept treatments as frequent as every 6 weeks, as has been the case for anti-VEGF therapies, although this is not the most desired practice either from the patient or physician perspective.

As a general rule, a device should offer advantages that are commensurate with the complexity or invasiveness of the procedure to implant it. Key advantages to the patient can include potential for long refill intervals, automated dosing, precise control of symptoms or disease progression via feedback sensors or mechanisms, and a high degree of safety or comfort. Key advantages should be offered to the physician as well. This would include worthwhile reimbursement for the procedure, low surgical risks, ease of technical operation of the device (i.e., remote charging, simple refill process, data uploads or downloads, custom settings for dosing, etc.) and flexibility of the design of the device to accommodate more than one therapeutic medication, whether refilled or dosed serially or concomitantly.

13.4.2  Intravitreal Delivery Through the Pars Plana

Along with the imminent commercialization of fully implanted intravitreal devices for long term for delivery of therapeutic agents, Weiner et al. (1995) proposed an alternative intravitreal delivery method in which a small refillable tack-shaped drug delivery device could be anchored across the sclera, having the delivery chamber in vitreous and an injectable refill port in the proximal end cap which was accessible under the conjunctiva (Fig. 13.5). Several styles of the device were presented in which single or dual reservoir chambers could be designed. In the dual reservoirs, a conduit between them (shown as element number 64 in Fig. 13.5) could optionally contain a one-way valve or diaphragm for flow control.

The above initial concept for pars plana anchored refillable systems with an accessible subconjunctival injection port was broadened further by Varner, De Juan, and colleagues a number of years later (Varner et al. 2002, 2004). In the earlier patent by these authors, a refillable reservoir was designed that had expansion capability upon filling, thus allowing for large loading capacity (Fig. 13.6). The latter reference describes a modification of the shape of the device to that of a coil which could deliver drug through several mechanisms including a hollow lumen of the coil to accommodate liquid refill though the proximal end. A nonrefill-coated style of this coil device termed I-Vation™ is currently being evaluated clinically for

Fig. 13.5  Refillable pars plana implanted tack device with refillable injection port under the conjunctiva. Reprinted from Weiner et al. (1995)

long-term delivery of steroid. The refillable tack and coil pars plana designs have been shown comparatively to a similar design approach but using a fully erodible format (Weiner 2007).

In general, the concept of a refillable device bridging through multiple tissues but containing an accessible injection port region under a layer of tissue has been extended to include other areas of the body. Ashton et al. (1998) and Watson et al. (2005) utilized similar techniques to describe a refillable system to reach inner portions of the brain with a compartmentalized device implanted under the scalp, through the skull and having a delivery tube extending distally into the target tissue (Fig. 13.7). The device further contained a semi-permeable membrane to control the rate of drug flow.

As opposed to having the entire refillable device located in the pars plana, Avery and Luttrull (1998) developed a design in which the majority of the device was located more posteriorly in the episcleral or sub-Tenon’s space, but from which a cannula would be directed from the device, penetrate through the pars plana, and terminate within the vitreous (Fig. 13.8). While the refill reservoir was more posteriorly located, the designed injection port region (element 122 in Fig. 13.8) was angled and encompassed a broad area to facilitate easier access with a needle. As part of additional embodiments, this design further incorporated either valveor baffle-type elements to reduce backflow, prevent flow out of the device during refill, or to allow for dosing by means of applying external pressure on the reservoir.

In a more concerted effort to bring the initial Avery concept to commercial utility, researchers at the University of Southern California and the California Institute of Technology have developed further engineering advancements of this style of refillable

Fig. 13.6  Refillable pars plana implanted device with expandable balloon type reservoir chamber within the vitreous. Reprinted from Varner et al. (2002)

device to automate its operation (Li et al. 2008; Lo et al. 2009; Saati et al. 2009; Pang et al. 2010; Avery et al. 2010). A primary added feature includes a microelectromechanical (MEMS) controlled electrolysis chamber which, when remotely activated, expands from the gas pressure, forcing drug-containing fluid out of a second adjacent reservoir and through the cannula which terminates either in the vitreous or anterior chamber (Fig. 13.9a, b). The enhancements also accounted for a hardened baseplate underneath the refill port to prevent a reinjection needle from penetrating through to the electronic componentry (Fig. 13.10) or via a stop built onto the shaft of the needle itself (Meng et al. 2009). Recent results with prototype devices containing glaucoma agents have shown controllability of anterior chamber dosing from the picoliter/minute to microliter/minute rates and IOP lowering efficacy in dogs comparable to controls (Avery 2010).