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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5394_Библиотеки_им_академика_М_И_Перельмана
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active agent out of the device is likely to be related to osmotic pressure or even
gravitational influence as opposed to hydraulic or mechanical forces. In that case,
the device chamber volume will reach some level of equilibrium with the external
tissue environment. Again, as in the above case for an active pump system, the
chamber content will contain a residual lower concentration of the active agent that
should be purged prior to a refill.
Using a passive system makes the ability to define the refill interval more challenging. In an active system, either through a known rate of fluid delivery or feedback measure of the chamber fluid volume, a calculated refill interval can be fairly
straightforward. However in a passive system which might maintain a constant fluid
volume with decreasing drug concentration, the required feedback information
could require more complex sensor approaches. Alternatively, well-powered clinical studies of patient efficacy could provide the information needed although this
may not be the most timely or efficient process.
13.2.5.3
The above discussion does not take into consideration the potential of a device to
be refilled with a solid dose form of the drug, such as reintroduction of a powder,
tablet, cylinder, or fiber into an already implanted device. As one might expect this
to be a more invasive approach overall, it would seem to be less attractive as a
design comparatively to an external refillable injection system like a pellet gun or
cartridge injector (Dinius and Huizenga 1984). Nonetheless, in consideration of
such a method, the solid material would still require an environment where fluid
can dissolve it. If the refilled solid is not directly open to the tissue on the output
side, but rather is housed in a fully enclosed chamber or container, the consideration of occupied solid volume vs. residual tissue fluid volume in that chamber
would need to be considered.
Solid Refill
13.2.6 Contamination Potential
Multiple refilling of an implanted reservoir offers potential to introduce infectious
and/or noninfectious contaminants, particularly if the injection port is located underneath the tissue (Renard et al. 2001). However, as long as sterile techniques are
applied in the refill operation, risk for introducing infection should be low. In a
study of 890 refill procedures in 25 patients with implanted intrathecal infusion
pumps, cultures of samples taken from extracted residual drug in the reservoir at the
last pump refill was negative for either aerobic or anaerobic bacteria (Dario et al.
2005). In the eye, the ability to flush surfaces with antiseptic such as povidone-
iodine and to have the patient apply a brief course of antibiotic prior to injection can
help reduce or eliminate any chance of introducing endophthalmitis.
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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.
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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
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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.
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
13.5). Several styles of the device were presented in
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Fig. 13.5 Refillable pars
plana implanted tack device
with refillable injection port
under the conjunctiva.
Reprinted from Weiner et
1995)
(
al.
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 valve- or
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
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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).
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Fig. 13.7 Refillable ported controlled release device design showing extended delivery tube (element
530) to reach distal tissue target. The injection reservoir contains a stop plate (element 539) to
prevent needle penetration. The stop plate further contains holes (element 538) to allow fluid diffusion.
A rate-limiting permeable membrane (element 550) prevents injection of small foreign particles
into the tissue. Reprinted from Watson (2005)
13.4.3 Episcleral Implantation for Trans-Scleral Delivery
Although injections into the anterior subconjunctival space have been a longstanding
practice dating back to the 1950s, particularly for injections of antibiotics or steroids,
the placement of drugs or devices in the posterior sub-Tenon’s space did not gain
favor until the beginning of the new millennium following new investigations utilizing
techniques to place a depot of the anti-angiogenic agent anecortave acetate above
the macula (Slakter et al. 2002; Dahlin et al. 2003). Concurrent with the development of an injection cannula for placement of such suspensions, a solid silicone based
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Fig. 13.8 Episcleral implanted device with drug reservoir connected to a cannula to deliver drugs
through the pars plana to the vitreous. The injection port region above the drug reservoir has an
angled and large surface area to facilitate needle placement for reinjections. Reprinted from Avery
and Luttrull (1998)
device was also devised as a means to put a more controlled rate form of the drug
near the macula (Yaacobi 2002; Yaacobi et al. 2003). This original device had a
length that followed along the border of the lateral rectus muscle and allowed placement of a drug load above the macular region with a distal end that was accessible
anteriorly near the limbus to allow for easy retrieval. Continued modifications of
that device were subsequently designed (Fig. 13.11) to allow for refill from an anterior
port position connected to pathways that would communicate fluid posteriorly
(Yaacobi 2006a). Furthermore, recognizing the possible need to more broadly distribute drug throughout the eye posterior, as might be required in disease states
such as dry AMD, a circumferential modification of the design was proposed by
Fig. 13.9 (a) Schematic of an episcleral implanted MEMS-controlled refillable drug delivery
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pump. Design elements include an electrolysis chamber (element 140) which is shown full
expanded from water hydrolysis and gas pressure, remotely controlled MEMS chip to generate
current for the water hydrolysis (shown at the base of the reservoir), adjacent fluid chamber containing the drug (element 130), and cannula from the drug chamber (element 120) which contains
a check valve (element 200). Reprinted from Pang et
placement of the MEMS-controlled refillable device. Positioning shows location between the rectus
muscles, a low profile to avoid irritation (<2
Reproduced from Lo et al. (2009). Copyright 2009 with permission from Springer
Fig. 13.10 Design features to assure proper placement of a 30-gauge reinjection needle in a refillable
port. Diagram (a) and sham device (b) show a hard polymer baseplate to prevent the needle from
penetrating components underneath the reservoir and a visible refill ring demarcating the port position.
Reproduced from Lo et al. (2009). Copyright 2009 with permission from Springer
al. (2010). (b) Illustration of profile and ocular
mm) and approximate cannula insertion point.
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