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13.3 Historical Influences
13.3.1 Infusion Pumps
Concepts for engineering of refillable infusion devices intended for ocular use have evolved from longstanding research and commercial development of systemic infusion pumps. From about 1980 onwards extensive research was put to developing fully implantable and refillable pumps which could achieve long-term systemic delivery of drugs for several key indications including therapy of cancers (Buchwald et al. 1980; Cohen et al. 1980, 1983a, b; Phillips et al. 1982), modulation of pain (Muller et al. 1984; Levy 1997) and control of diabetes (Selam et al. 1982; Prestele et al. 1983). Devices like the SynchroMed® (Medtronic, Inc.) and other similar designs allowed for percutaneous or abdominal implantation with accessible ports for refill or direct infusion via cannula connection to the pump (Fig. 13.3). Such pumps were made to contain large volumes (e.g., 10–40 mL) and deliver therapeutic levels for minimum periods of 2–3 weeks prior to refill, depending on rate needed and concentration of drug used. The driving force in some of the designs relies on gas pressure to drive fluid from the reservoir into the tubing which is then subject to peristaltic pumping. The fairly large size of such devices prompted others to begin looking at approaches to reduce pump sizes through engineering of different infusion mechanisms. An example of one such method was described by Roorda (2001) who describe a rotating arm which applies compressive force to the dispensing path.
13.3.2 Glaucoma Drainage Devices
The foundation for experimental placement of many current ophthalmic drug delivery pump designs stems from studies examining drainage devices to reduce intraocular pressure. The first successful device to gain acceptance for this purpose was the
Fig. 13.3 SynchroMed implantable infusion pump (Medtronic, Inc.)
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design introduced by Molteno (1969) in which a plate portion of the device that was implanted in the anterior subconjunctival space maintained the patency of the filtration reservoir, thus overcoming the issue of flow restriction due to subconjunctival fibrosis. Since that time there have been a variety of styles (including well-known commercial styles as the Baerveldt or Ahmed drainage valves) which are mainly implanted in the posterior subconjunctival or sub-Tenon’s space (Lim et al. 1998). Important knowledge gained from these historical studies includes tissue response to various biomaterials as well as function and placement of valved drain systems. For example, early setons, tubes and preliminary designs did not address control mechanisms to prevent development of hypotony, an important factor to consider when the device bridges multiple compartments in the eye. In line with this, glaucoma valve and shunt studies contributed to an understanding of design options to achieve optimum valve cracking pressures to assure continued flow without impacting backflow or drop in the internal intraocular pressure (Setabutr et al. 2006).
13.3.3 Pioneering of Refill Procedure in the Eye
As of this writing, it is important to note that there is yet to be any commercialized refillable ophthalmic device. While the current technology for ophthalmic refillable systems is actually in very early stages, particularly relative to initial human clinical evaluations, this is not a result of such concepts being new. More than 30 years ago, Refojo, Liu and colleagues (Refojo et al. 1978; Liu et al. 1979, 1983; Refojo and Liu 1981) described episcleral implanted refillable silicone devices for treatment of intraocular malignancies using 1,2-bis [2-chloroethyl]-1-nitrosourea (BCNU). A silicone balloon was constructed by cementing two silicone sheets around a cannula that formed a reservoir accessible by the cannula (Fig. 13.4). Following episcleral implantation the device was refilled through the cannula with drug dissolved in oil or ethanol, which diffused rapidly from the device leaving drug depot in the reservoir. Even though the device was elemental in its construction, it demonstrated in principle that episcleral implantation of a device having an external refill port could function as a potential mode of delivery. Surprisingly, despite these seminal reports, the potential of ophthalmic refillable systems went unrealized for many years and further interest in possible designs did not surface until the 1990s. This is perhaps related to a paucity of drugs deemed viable at the time for such an approach, the lack of knowledge concerning validation of drug efficacy by intraocular administration and a diversion of attention to the learning curve associated with developing more conventional intravitreal implant approaches eventually leading to products such as the Vitrasert® (Bausch and Lomb), Retisert® (Bausch and Lomb), and Ozurdex® (Allergan) devices. It can be noted that as ancillary to the development of the Ozurdex (Posurdex) system, variations of that implant approach were also reported using a drug core filled into a hollow impermeable cylinder with one or more orifices for drug release (Wong et al. 2001). Within the context of that variation, provision for refillability was discussed as an option, although specific enabling features were not described.