Biomaterials in Ophthalmology

Rachel L Williams, Hannah J Levis, Rebecca Lace, Kyle G Doherty, Stephnie M Kennedy, and Victoria R Kearns, University of
Liverpool, Liverpool, United Kingdom
© 2019 Elsevier Inc. All rights reserved.

Introduction 289
Refraction 289
Contact Lenses 289
Intraocular Lenses 290
Space Filling 291
Vitreous Substitutes 291
Scleral Buckles 292
Orbital Implants 292
Flow Control 292
Electric Stimulation 293
Tissue Regeneration 294
Natural Scaffolds 295
Biological Polymers 296
Synthetic Polymers 296
Conclusion 297
References 297

Introduction

Innovations in biomaterials science and engineering have the potential to make a significant contribution to the development of
treatments for ophthalmic diseases and thus to reduce the burden of vision loss on the global community. The loss of vision
has major social and economic consequences not only to the individual but also to society at large, and with the increasing age
of the population, this will have greater consequences. There are functional requirements of the eye and visual system that allow
vision to occur, and various diseases and trauma can disrupt these processes. Biomaterials have a role in addressing several of these
functional problems such as refraction, space filling, flow control, electric stimulation, and tissue regeneration. This article will
discuss the biomaterials used in each of these categories.

Refraction

The cornea is the transparent window that allows light to enter the eye. It also has a major role in focusing light, providing about
80% of the eye’s refractive power, with the rest being achieved by the lens. To overcome problems with the ability of the eye to
refract the light and focus it onto the retina, biomaterials have been used in the form of contact lenses and intraocular lenses.

Contact Lenses
Contact lenses not only are traditionally used to correct refractive error but also can be used to assist wound healing as a bandage
contact lens or, alternatively, as a drug reservoir. The material properties that must be considered for contact lens selection are high
oxygen permeability so oxygen can reach the cornea and prevent vascularization, high water content for tear film wettability and
comfort, and resistance of protein/lipid/mucus deposits on the contact lens (Refojo, 1996). There are four main groups of materials
used for contact lenses; these can be classified as either “hard” or “soft.” Soft flexible contact lenses include hydrogels (based on
poly(hydroxyethylmethacrylate) (pHEMA)), silicones, and silicone hydrogels. Gas-permeable materials (usually made from fluo-
rosilicone acrylates) are rigid and classed as hard contact lenses. The largest proportion of contact lenses on the market today are
silicone hydrogel at 64%. These lenses combine different ratios of each material to achieve both the benefits of the high oxygen
permeability from the silicone and increased wear comfort from the hydrogel (Caló and Khutoryanskiy, 2015; Kirchhof et al.,
2015). Soft contact lenses have also been used for bandage contact lenses; these aim to prevent necrosis after surgery and facilitate
wound healing by protecting the eye from external assault and sources of infection; they also keep the ocular surface hydrated and
relieve pain by isolating friction during blinking. An example of when these are routinely used is after keratoprosthesis (Carreira
et al., 2014; Thomas et al., 2015). A bandage contact lens that offered a therapeutic antimicrobial effect could be beneficial as
a replacement for conventional antimicrobial eye drops in treating infectious keratitis. Gallagher et al. have demonstrated this
with a hydrogel synthesized from poly-ε-lysine with additionally bound biomolecules to achieve a hydrogel with optimized

Encyclopedia of Biomedical Engineering, Volume 1 https://doi.org/10.1016/B978-0-12-801238-3.11034-7 289

290 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

mechanical and antimicrobial properties (Gallagher et al., 2016). Another potential application for contact lenses is their use in
drug delivery to the front of the eye; this would be beneficial as there is a low bioavailability of ophthalmic eye drop (about
5%) due to the high drainage via the tear duct or down the cheek. One of the challenges is to achieve a sustained therapeutic release
of the drug over a period of time. Simple methods involve soaking commercial hydrogel contact lenses in solutions containing
drugs; however, the release profile of the drug is uncontrolled, leading to an initial high overdosing period over a few hours fol-
lowed by a long underdosing period, making them unsuitable for long-term release. An alternative method is to immobilize drugs
onto the surface of hydrogel contact lenses that may require modification using polyethylene glycol (Kirchhof et al., 2015; Xinming
et al., 2008). Other methods to trap drugs and release them from contact lenses include molecular imprinting, colloid encapsula-
tion, and polymeric nanoparticles (Dixon et al., 2015; Maulvi et al., 2016). Ciolino et al. examined the properties of a copolymer of
poly(hydroxyethylmethacrylate) and methacrylic acid (pHEMA/MAA) contact lens that encapsulated a poly(lactic-co-glycolic) acid
(PLGA) film that incorporated the glaucoma drug latanoprost. They demonstrated that as the PLGA drug film degraded, the contact
lens delivered a therapeutic amount of the drug over a 4-week period in vivo without any signs of cytotoxicity (Ciolino et al., 2014).
Drug delivery in the eye, and the biomaterials used in general, is a large topic and will not be covered further in this article.

Intraocular Lenses
Cataracts are the leading cause of preventable blindness worldwide. During surgery, the cloudy lens is removed from its capsular bag
and replaced by a polymeric intraocular lens (IOL). Over the years various polymers and designs have been used for IOLs, in an
attempt to prevent postoperative complications associated with scarring. The polymers used can be grouped into three main groups:
hydrophobic acrylic (e.g., phenylethyl methacrylate (PEMA) and phenylethyl acrylate (PEA)); hydrophilic acrylic (e.g., poly hydrox-
yethylmethacrylate (pHEMA)); and silicone (e.g., poly dimethylsiloxane (PDMS)). Due to the nature of the surgery, the chosen
material should be foldable, so it can be inserted into an incision of 3–4 mm diameter or less to minimize the damage caused
by the surgery and postoperative scarring. How the IOL responds to the native tissue plays a key role in scarring. Postoperative
complications occur when residual lens epithelial cells migrate onto the previously cell-free posterior capsule in which the lens
is housed. Once here, these cells dedifferentiate into fibroblast-like cells causing the posterior capsule to wrinkle and disrupt the
path of light to the back of the eye (Apple et al., 1992) (Fig. 1). This is known as posterior capsule opacification (PCO). The inci-
dence of PCO varies between studies, both the IOL material (hydrophobic vs hydrophilic) and design (sharp- or round-edged IOLs)
can play a part in this (Auffarth et al., 2004; Yuen et al., 2006). Although IOL material and design choice may slow down the devel-
opment of PCO, it does not prevent it. Rønbeck et al. demonstrated in a 12-year postoperative review of three IOLs including
a round-edged heparin surface-modified poly(methyl methacrylate) IOL, a round-edged silicone IOL, and a sharp-edged hydro-
phobic acrylic IOL that there was no significant difference in the incidence of PCO after 12 years between the acrylic and silicone
IOL regardless of edge shape. There was, however, a significant difference short term (5-year postsurgery), in which patients with
acrylic IOLs had significantly less PCO than those with silicone IOLs (Rønbeck and Kugelberg, 2014). With an increasing ageing
population, other methods need to be investigated to prevent the long-term effects of PCO; one possible strategy could be the
use of IOLs as a drug delivery system (see Liu et al., 2013).
Injectable gel-like polymers, based on polysiloxane, have been investigated as an alternative to conventional IOLs. The gel struc-
ture can be injected inside the capsule bag, leaving it intact. The gel conforms to the shape of the capsular bag, while the capsular bag
supports the gel. These gels have the added benefit of accommodation, similar to the natural lens, which is not fully possible with

Fig. 1 Photograph of a donor eye with intraocular lens implant and early posterior capsule opacification formation. Early fibrosis (white arrows) was
observed as scar tissue at the periphery and the development of Soemmering’s ring (red arrow).
 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology 291

the conventional IOLs (de Groot et al., 2001). By varying Young’s modulus of polysiloxane gels to 0.8 kPa, similar to the native
human lens (1 kPa), lenses can undergo changes in refractive power during equatorial stretching, which simulates accommodation
and have a higher lens power than the age-matched natural lenses (Koopmans et al., 2003). However, the incidence of PCO remains
a problem and in addition, Nd:YAG laser capsulotomy, which is the removal of the opaque posterior capsule via a laser, cannot be
performed as this would affect the accommodation capabilities of the soft lens. Alternative methods to eliminate PCO have been
investigated, for example, aggressive cytotoxic chemicals to kill remaining LECs prior to injecting the gel-like lens (van Kooten et al.,
2006); however, due to the level of aggression needed to kill all remaining LECs, further complications of cornea opacification have
been observed (Koopmans et al., 2011).

Space Filling
Vitreous Substitutes
Replacement of the vitreous humor is required if the native vitreous body needs to be removed, either to facilitate surgical treatment
for retinal detachment or if the vitreous body itself is compromised due to other conditions including infection, tumor, or trauma
(Kleinberg et al., 2011). Vitreous substitutes also have the potential to be used as drug delivery devices. The vitreous humor is
predominantly composed of interpenetrating networks of collagen fibrils and hyaluronan molecules (with various other compo-
nents, including cells) forming a clear hydrogel. It provides support to the surrounding structures, absorbs mechanical trauma,
and is involved in the circulation and regulation of oxygen, metabolites and nutrients. The composition and structure of the vitreous
humor and vitreoretinal interface has been described in detail by Sebag (1998, 1992).
Silicone oils (Giordano and Refojo, 1998) were first used to treat retinal detachment in the 1960s and have been more
commonly used since the availability of vitrectomy. They are currently the only class of vitreous substitute available for long-
term use (it is usually removed within 3–6 months, although there are patients with permanent silicone oil (Morphis et al.,
2012) but are used much more in Europe than in the United States (D’Amico, 2016). The conventional belief is that their primary
mode of action is to block the flow of fluid through the retinal breaks, excluding the inflammatory factors that can lead to the forma-
tion of scar tissue that can cause the retina to distort and detach (Wong and Williams, 2005). The use of silicone oil has, however,
been associated with the development of cataract (Heimann et al., 2008) and corneal endothelial graft failure (Friberg and Guibord,
1999). Early formulations caused problems relating to the presence of low-molecular-weight components (Pastor et al., 1998); all
currently available products are highly purified to remove these components.
Silicone oils have a propensity to emulsify. This is likely to be due to a combination of high shear forces, insufficient interfacial
tension between the oil and aqueous phases in the eye, and the presence of proteins that both lower the interfacial tension and
stabilize emulsified droplets. The formation of emulsions affects the passage of light but, more significantly, is associated with
the development of complications such as glaucoma (Ichhpujani et al., 2009) and migration into the anterior chamber (Light,
2006). It has been suggested that emulsification is underreported, as droplets that can be observed clinically are relatively large
compared with those that can be measured from samples retrieved from patients but studied in vitro (Chan et al., 2015). A number
of strategies have been developed to attempt to reduce emulsification, including the use of oils with higher shear viscosity (Scott
et al., 2005; Chan et al., 2011); there are no randomized clinical trials, however, showing superior emulsification resistance of
5000 mPa$S oil over 1000 mPa$S oil. A more recent strategy has been the development of silicone oils with increased extensional
viscosity, achieved by adding a small percentage of a high-molecular-weight component to standard 1000 mPa$S oil (Williams
et al., 2010). These oils, which are in clinical use, also experience shear thinning, making them relatively easy to inject (Williams
et al., 2011).
Silicone oils have a lower density than the aqueous solutions that fill the remainder of the cavity; thus, they are unsuitable for
treatment of pathology in the lower part of the vitreous cavity. A range of “heavy” silicone oils have been developed, and a few are in
clinical use (Heimann et al., 2008). They are based on standard silicone oil with the addition of perfluorohexyloctane or a partially
fluorinated olefin. The resulting oils, which have densities of 1.06 and 1.02 g/cm3, respectively, are reported to result in anatomical
success, but complications such as emulsification exist (Ozdek et al., 2011; Wickham et al., 2010). A more recent development is the
combination of the addition of perfluorohexyloctane and the high-molecular-weight additive, resulting in a “heavy oil” that should
have increased emulsification resistance (Caramoy et al., 2015), although a large body of clinical evidence is not yet available for
this tamponade. An alternative strategy, which aims to take advantage of the light and oxygen diffusion properties of silicone oil
while mimicking the natural structure of vitreous and vitreoretinal interface, is to contain the silicone oil (or other fluid) within
a silicone rubber capsule within the eye (Lin et al., 2012; Yang et al., 2014). This technique has been tested in clinical trials, although
has not been widely adopted.
Hydrogels (Swindle-Reilly et al., 2016; Chirila et al., 1998; Su et al., 2015) are the most widely researched alternative to silicone
oils, because of their potential to more closely mimic the structure of the vitreous humor. Hydrogels should be designed to have
appropriate physical, chemical, and biological properties, including the ability to gel in situ; however, to date, none has made it into
clinical practice. Unlike silicone oils, they are not able to exert a significant tamponade effect (Liang et al., 1998), so are limited to
conditions that require space filling and as drug delivery devices. Many of them are reported to degrade once implanted into the
vitreous cavity. Hyaluronan- and collagen-based gels have been widely investigated, but even following the addition of other
components and cross-linking, these materials do not have the required physical properties and have a lower density than water,
limiting their use for tears in the upper area of the vitreous cavity or are still susceptible to degradation in vivo (Liang et al., 1998;
292 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

Schramm et al., 2012; Pruett et al., 1979; Barth et al., 2016). Work on various other natural and synthetic polymers, including poly-
acrylamide (Santhanam et al., 2016), polyethylene glycol (Annaka et al., 2011), and chitosan (Yang et al., 2008), has been reported.

Scleral Buckles
Scleral buckles are devices that are placed within or on the sclera and are used to treat retinal breaks that are associated with retinal
detachment. The principle is that by displacing the sclera, vitreoretinal traction is reduced, and fluid, that includes inflammatory
factors, is moved away from the retinal breaks. Although it remains a successful treatment, with clinical outcomes comparable
with other treatments (Khan et al., 2015), it is being used less frequently. Devices based on silicone are the only materials that
are currently used clinically. They may be solid structures, often bands between 2 and 5 mm wide (Schepens and Acosta, 1991),
or sponges. One of the advantages of silicone is that it does not encourage the attachment of tissue, which can cause complications
if the implant needs to be removed. Furthermore, they are sufficiently tough and pliable to allow the surgeon to manipulate them
during implantation. The tendency of other materials to allow tissue attachment is one of the reasons why they are not clinically
successful. Hydrogels, biologically derived polymers and degradable polymers have insufficient mechanical strength for the
required duration (Baino, 2010).

Orbital Implants
It is sometimes necessary to remove the eye of the patient, for example, following cancer, severe infection, or trauma. An orbital
implant (Baino and Potestio, 2016; Sami et al., 2007) can be used to restore the resulting cavity, which is important for aesthetic
and psychological reasons. Orbital implants can be classified as integrated or nonintegrated. From a materials perspective, this can
be linked to whether the implant surface is porous or not, although some are designed to allow tissue ingrowth on the posterior
surface while usually having a smooth anterior surface. A recent Cochrane review (Schellini et al., 2016) has been unable to deter-
mine whether either strategy is better. Polymethyl methacrylate is in clinical use to produce orbital implants of various designs
(Baino and Potestio, 2016) as it has a good track record and is cheap. Polyethylene, particularly in porous form with a smooth ante-
rior surface or coating to reduce irritation to surrounding tissue such as the conjunctiva and to allow connection of extraocular
muscles, is also used (Karesh et al., 1994; Jung et al., 2012). Porous silicone (Son et al., 2012) and expanded polytetrafluoroethylene
have been investigated (Dei Cas et al., 1998), but are not used clinically.
Ceramic implants (Baino and Vitale-Brovarone, 2015), both hydroxyapatite and alumina, are used in various clinically available
implants (Suter et al., 2002; De Potter et al., 1994; Jordan et al., 2003), both allowing desirable tissue ingrowth. Promising early
results have also been reported for patients receiving a bioactive glass–ceramic implant (Crovace et al., 2016). Optimizing micro-
structure and topography may be important in determining and enhancing the clinical response (Mawn et al., 1998; Patel et al.,
2010), although this is not yet widely studied. Composites of the earlier materials have been investigated, although many have
not been successful in patients. In particular, bioactive ceramics have been used as coatings to encourage tissue ingrowth. Those
that have made it into clinical use include one based on hydroxyapatite and silicone, and another based on porous polyethylene
and 45S5 bioglass (Ma et al., 2011).

Flow Control

Normal eye pressure ranges from 12 to 22 mmHg. The intraocular pressure is maintained in the normal range by the flow of
aqueous humor, which is produced by the ciliary body, from the back of the eye into the anterior chamber through the pupil. It
then flows out of the eye through the trabecular meshwork into Schlemm’s canal and is absorbed into the bloodstream. The produc-
tion and flow of the aqueous humor is an active, continuous process that is needed for the health of the eye. If the flow is restricted,
pressure builds up in the eye, which can cause damage to the optic nerve, leading to vision loss.
Glaucoma is usually characterized by a high intraocular pressure that may be due to the reduction of fluid flow through the
trabecular meshwork or in the collector channels or venous plexus further downstream. In many cases, glaucoma can be treated
with eye drops that cause a lowering of the intraocular pressure either by reducing the amount of aqueous humor produced or
by increasing its outflow. In some situations, however, this is not sufficient or eyedrops are no longer functional, and alternative
strategies are needed to ensure the pressure remains in the normal range. In general, this involves surgery to produce a channel
through the obstructed tissue to allow outflow of the fluid. Minimally invasive glaucoma surgery has been designed to make glau-
coma surgery simpler to perform with less trauma to the eye and a more easily reproducible technique so that the procedure is avail-
able to all ophthalmologists rather than just glaucoma specialists (Manasses and Au, 2016). This has resulted in several different
designs of glaucoma microstents that can be classified by the targeted outflow destination: into Schlemm’s canal, the suprachoroidal
space, or the subconjunctival space. The iStent, which is 1 mm long and has a lumen of 120 mm, is designed to bypass the trabecular
meshwork and allow outflow directly into Schlemm’s canal. It is made from a heparin-coated titanium alloy (Ti6AI4V), and it is
possible to insert two or three at the time of cataract surgery. Placement of the istent in conjunction with cataract surgery in
mild to moderate glaucomatous eyes has been shown to cause a moderate reduction in IOP and reduce the dependency of the
patient on medication (Manasses and Au, 2016). The Hydrus Microstent is similarly a trabecular meshwork bypass device. It is
much longer at 8 mm and is designed to follow the curve of Schlemm’s canal preventing its compression. It is manufactured
 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology 293

from NiTi alloy and is fenestrated along its length to aid outflow of aqueous into Schlemm’s canal. One year clinical results show
that this can maintain a reduced IOP, rarely achieving less than 15 mmHg, and a reduction in use of medication over at least
12 months. The Cypass stent is designed to bypass the trabecular meshwork and provides a direct outflow channel into the supra-
choroidal space. It is made from polyimide and is 6.35 mm in length with a 300 mm lumen with fenestrations along its length to
facilitate outflow. Like the Schlemm’s canal devices, IOP is rarely observed below 15 mmHg and generally resides above 16 mmHg.
The iStent Supra uses a similar approach and is a 4 mm tube made from fenestrated polyethersulfone with a Ti sleeve.
The more traditional way to release fluid from the anterior chamber is into the subconjunctival space. There are two glaucoma
microstents that are designed to take advantage of this route and bypass all potential outflow obstructions. The XEN 45 is manu-
factured from porcine-derived gelatin cross-linked with glutaraldehyde. It is a 6 mm long tubular structure with a lumen of 45 mm
that has been designed specifically to control the rate of fluid flow to maintain the correct IOP.
The InnFocus MicroShunt (Fig. 2) similarly drains into the subconjunctival space. It has been through various design iterations
to ensure as little trauma to the tissues and a lumen size that minimizes hypotony (Pinchuk et al., 2017). The final design resulted in
a stent that is 8.5 mm long with a 70 mm diameter lumen. The material that it is manufactured from was a key part of the design
process. The objective was to design a synthetic thermoplastic elastomer that is biostable and caused less of an inflammatory
response than conventional materials. The material is synthesized at InnFocus and is a triblock copolymer of a soft polyisobutylene
central block with glassy polystyrene end blocks called poly(styrene-block-isobutylene-block-styrene) or SIBS. It has enhanced
biocompatibility and long-term stability resulting in less inflammation than other materials. A lowering of the IOP
to  14 mmHg was recorded after 3 years in 95% of the patients (Manasses and Au, 2016).

Electric Stimulation

Damage to retinal tissue via various disease mechanisms has led to research to attempt to augment or replace the function of
damaged tissues using retinal implants. Patients in many of the clinical trials that have been run to date suffer from retinitis pig-
mentosa (RP), a group of hereditary diseases that damage the photoreceptor cells of the outer retina but leave the nerve cells of
the inner retina intact. Retinal implant devices provide electric stimulation to these remaining nerve cells that transmit the signals
along their axons, which form the optic nerve, to the visual cortex in the brain.
The devices aim to capture light and convert this to an electric pulse that is delivered to nerve cells, particularly the ganglion cells.
These electric impulses cause patients to perceive flashes of light called phosphenes. Many groups are investigating various different
approaches to light or image capture, processing and conversion to electric impulses, and electrode design and location (Maghami
et al., 2014; Ha et al., 2016). The Alpha IMS, developed by Retinal Implant AG based in Reutlingen, Germany, uses a CMOS active
pixel sensor array that is implanted subretinally, beneath the transparent retina, replacing the defunct photoreceptor cells. It received
CE marking for sale in Europe in 2013, and the latest version, the Alpha AMS, obtained CE marking in 2016. The devices contain
a photodiode-amplifying microelectronics electrode set within each pixel of the array. Incident light on the photodiode is converted
and amplified into an electronic pulse and is delivered via the electrodes to nearby nerve cells. The circuitry is created using a CMOS
process. This is encapsulated by an insulating material, such as a polymer, that will prevent fluids in the eye from shorting the
circuitry and thus causing device failure. Electrodes are connected to the circuitry and made of conducting noncorrosive materials,
such as TiN or IrO (Graf et al., 2009). Work by this group in 1999 investigated the biocompatibility of various semiconductor and
electrode materials including SiO2, Si3N4, TiN, and Ir (Guenther et al., 1999). Rat retinal cells were seeded onto the materials, and
biocompatibility was determined by examining cell attachment and growth. Cells grew on all materials, and although there were
fewer cells on TiN compared with Ir, it appears that this material is still used for electrodes. The chip is mounted on a metallized

Fig. 2 Diagram of the InnFocus MicroShunt in situ in the anterior chamber angle. Provided by InnFocus Inc.
294 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

polyimide ribbon cable that exits the eye and extends toward an induction coil located behind the ear, similar to a cochlear implant.
The coil must be hermetically sealed, usually in silicone or ceramic, similar to other implants. Power is wirelessly transferred from an
external supply to this coil and via the ribbon cable to the chip. Polyimide has previously been demonstrated as a biocompatible,
flexible substrate for electrode arrays (Klinge et al., 2001; Seo et al., 2004; Richardson et al., 1993).
The Argus II (Fig. 3), developed by Second Sight based in Sylar, CA, the United States, is an epiretinal device that has been
granted permission to be marketed in the United States and Europe. It consists of a pair of glasses with a mounted camera that
is connected to a small processing unit. Images are captured and processed outside the eye, and then, information and power
are transmitted by transcranial induction to a paired coil and electronics unit that is held in place outside of the eye by a scleral
band. The scleral band and antenna are encased in silicone (Second Sight Medical Products, 2013), which functions similarly to
scleral buckles mentioned previously. The electronics unit is hermetically sealed and sends information and electric pulses, via
a ribbon cable that passes through the eye, to an electrode array attached to the inner surface of the retina. The conducting wires
of the electrode cable are encased in polyimide, but the end of cable and the electrode array are coated with silicone (Second Sight
Medical Products, 2013). Electric impulses are delivered to the retina via platinum electrodes. The electrode array is held in position
with a spring-loaded titanium alloy retinal tack (de Juan et al., 2013).
One of the drawbacks of the systems outlined earlier and those similar is the fact that information is captured outside the eye and
needs to be transferred, along with power, from an external source to the inside of the eye. A device that was contained completely
within the eye at the site of operation would be beneficial as image capture would move with the patients’ eye, and not their head as
with external mounted image capture devices and would not necessarily require materials to pass through different layers of tissue.
Optoelectronic polymers are materials that could produce these benefits and are currently being investigated for their use in electric
stimulation of the retina. These polymers create an electric impulse when struck by photons of light but are much more flexible
compared to stiff silicon-based photovoltaic materials. Work using regioregular poly(3-hexylthiophene) blended with or without
phenyl-C61-butyric acid methyl ester as a semiconducting layer and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) as
a conductive layer has shown promising results. They have been demonstrated to restore light sensitivity to diseased explanted
rat retinas (Ghezzi et al., 2013) and are stable for at least 5 months when implanted into rat retinas (Antognazza et al., 2016). These
materials show promise, but much more work is required.

Tissue Regeneration

The regeneration of damaged tissue using tissue engineering strategies is being investigated for tissues throughout the eye. The two
major areas are the ocular surface, involving the cornea and conjunctiva, and the retinal pigment epithelial layer under the retina.
The precise functional requirements are different in either case, but there are also many similarities.
In cases of corneal damage, the current treatment is replacement of the dysfunctional tissue with a corneal transplant; however,
due to the high demand for tissue, there is a shortage of donors, and so tissue engineering approaches are needed to provide alter-
native options. The cornea is composed of five layers (Fig. 4A): the outermost epithelial layer with its underlying Bowman’s
membrane; the stroma whose regular arrangement of collagen fibers is responsible for the transparency of the cornea; and finally,
the most posterior layer, the monolayer of corneal endothelial cells sitting on the Descemet’s membrane. The cornea is continuous
with the tough, opaque sclera; therefore, it plays a key role in maintenance of the protective outer layer of the eye but must be trans-
parent to allow light to reach the retina. The conjunctiva (Fig. 4B) is a transparent membrane that covers the inner surface of the
eyelids and extends over the sclera to meet the limbus at the periphery of the cornea. It is a stratified, nonkeratinized epithelium that
serves as a barrier to protect underlying tissue but also as a mucous membrane. Goblet cells within the epithelium secrete mucins
that maintain the tear film protecting the cornea from infection and desiccation. One of the striking features of the conjunctiva is the
flexibility of the continuous tissue over the large and cavernous regions of the eyelids.

Fig. 3 A cartoon of an implanted Argus II epiretinal implant, developed by Second Sight. Information and power are transmitted to the electronics
case via the antenna. From the electronic case, electric impulses are sent to various electrodes on the array, depending upon the information
received. The electrode array is pinned to the internal surface of the retina.
 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology 295

Fig. 4 (A) Schematic showing the five layers of the cornea; outermost epithelium, Bowman’s layer, stroma with interspersed keratocytes, Desce-
met’s membrane and most posterior endothelial layer that contacts the aqueous humor of the anterior chamber (B) conjunctiva comprises a non-
keratinized, stratified squamous epithelium interspersed with goblet cells.

Disease and disorder can affect each of the components of the ocular surface, and the latest surgical techniques often target the
specific layer affected. Therefore, recent tissue engineering strategies have followed the same path with most attempting to combine
an ex vivo expanded cell population with a suitable material for transplant that meets the particular requirements of the damaged
tissue.
Retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) cause damage to the retinal
pigment epithelium. The retinal pigment epithelium is a monolayer of cells that sits beneath this neural retina on a thin basement
membrane known as Bruch’s membrane that separates it from the blood vessels in the choroid. The retinal pigment epithelial (RPE)
monolayer of cells is the crucial component of the support tissue of the retina and is known to play a key role in maintaining its
normal functions. In particular, the RPE cells phagocytose the spent outer segments of the photoreceptors. Damage to, or loss of RPE
cells can have serious consequences, particularly as its ability to support the overlying photoreceptors will be compromised leading
to irreversible vision loss. Cell transplantation of RPE cells offers a potential therapy to prevent photoreceptor loss. Successful cell
transplantation requires the precise delivery, appropriate cell organization, alignment, integration, and differentiation of cells to
form a functional epithelial monolayer.

Natural Scaffolds
The complex structure of the corneal layers and cellular basement membranes pose a significant challenge to replicate. Some regen-
erative medicine strategies aim to circumvent this problem by simply reusing these perfected structures as starting scaffolds. Corneal
stroma comprises predominantly type I collagen fibers arranged in a precise orthogonal fashion interspersed with keratocyte cells.
Decellularization of stromal tissue retains the precise structure of the scaffold allowing it to be transplanted in cases of stromal scar-
ring with reduced risk of rejection (Choi et al., 2011).
A commonly trialed natural material in ocular surface tissue engineering is amniotic membrane, the innermost layer of the fetal
membrane. This is because it has some very useful characteristics such as anti-angiogenic and antiinflammatory properties, its rela-
tive elasticity and flexibility, and its favorable basement membrane features that are conducive to epithelial cell growth (Rahman
et al., 2009). For these reasons, it has been used in conjunctival reconstruction, as a carrier/substrate for corneal epithelial layer
transplantation and also as a substrate for corneal endothelial cell expansion. As is the case with any biological tissue, there is signif-
icant donor variation in terms of thickness and related degradation rate and the presence of anti-inflammatory cytokines. In addi-
tion, the tissue preparation protocols are not standardized between centers, which make clinical data relating to its use in tissue
engineering difficult to interpret as the membrane composition may differ widely.
An alternative to tissue engineering using a biomaterial substrate is injected cell therapy, which is currently being explored as
a potential therapy for damaged corneal endothelium (Okumura et al., 2012). This approach involves simply injecting a cell suspen-
sion into the anterior chamber and allowing the monolayer to form in situ on the posterior corneal surface. There are some concerns
about this approach regarding the ultimate destination of the injected cells at aberrant ocular sites. Therefore, due to the relative
simplicity of the corneal endothelium, attempts have been made to engineer a scaffold-free endothelial cell sheet ex vivo using a ther-
moresponsive poly (N-isopropylacrylamide) (pNIPAAm) substrate for cell growth. At 37 C, the surface is hydrophobic, and cells
can adhere, but when the temperature is lowered to 20 C, the polymer chains of pNIPAAm hydrate to form an expanded structure
detaching the cells as an intact sheet without the need to use enzymatic digestion (Tang et al., 2012). The major advantage of a scaf-
fold-free sheet is that they have been associated with fewer inflammatory responses that are typically observed in the biodegradation
of natural scaffolds; however, delivery of the intact sheet to the site of transplant still remains a significant challenge.
In the subretinal position, injection of RPE cell suspensions and tissue grafts have resulted in poor cell survival and low integra-
tion of cells, with disorganized and incorrectly localized grafts and difficulty in retaining the cells in the targeted site (Tomita et al.,
2005; MacLaren et al., 2006; Klassen et al., 2004). However, this continues to be a strategy employed in current clinical trials (Kim-
brel and Lanza, 2015). Transplantation of RPE cells onto alternative natural material including decellularized Bruch’s membrane,
296 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

amniotic membrane, Descemet’s membrane, and lens capsule (Hartmann et al., 1999; Lee et al., 2007; Turowski et al., 2004) that
mimic the mechanical properties of natural tissue has been investigated with varying levels of success. Limitations with these
approaches arise due to the limited expansion of cells and availability of donor tissue. Scaffold-free approaches using pNIPAAm,
similar to that described earlier for corneal endothelium, have been also reported (Yaji et al., 2009).

Biological Polymers
Collagen is widely used in corneal tissue engineering since the basement membranes of both the corneal epithelial and endothelial
layers, as well as the stroma, are abundant in collagens including types IeV. Many research groups have developed stromal tissue
equivalents using animal-derived collagen (Levis et al., 2010, 2013), but an alternative strategy has been reported that uses recombi-
nant type III human collagen cross-linked with carbodiimide. This material was designed to mimic the collagenous extracellular
matrix of the stroma to stimulate in situ repopulation of the graft with keratocytes and corneal nerves. The material has sufficient
tensile strength and elasticity and allows keratocytes to repopulate the graft over time in addition to maintaining a tear film on the
surface (Liu et al., 2008). These hydrogels have since been trialed in clinical studies with four patients all displaying stable corneal
regeneration 4 years after implantation (Fagerholm et al., 2014). These materials have also been investigated for conjunctival epithe-
lial and goblet cell growth (Table 1) (He et al., 2016).
Other natural materials that have been used for ocular surface repair are chitosan, silk fibroin, and fibrin. The latter forms the
basis of Holoclar, the first stem cell-based medicinal product to be approved for use in Europe. Human limbal stem cells are culti-
vated on a fibrin (thrombin and fibrinogen) membrane and transplanted onto the ocular surface to repair damage in cases where
the native limbal stem cell population has been destroyed by chemical or thermal burns. The fibrin substrate supports the expansion
and growth of a healthy epithelial layer and, after transplantation, slowly degrades leaving the stem cells to seed the regrowth of
a transparent cornea. One additional advantage of the fibrin gels is that its constituents can be produced from autologous plasma
(Pellegrini et al., 2016).
In vitro studies have shown that collagen scaffolds are capable of supporting RPE cell adherence and proliferation, with pheno-
typic characteristics of differentiated RPE cells (Malafaya et al., 2007; Karwatowski et al., 1995). In vivo studies in rabbits have
shown biocompatibility with no immune rejection or inflammation and the ability to phagocytose photoreceptors (Thumann
et al., 1997).

Synthetic Polymers
Synthetic materials have an advantage over natural materials because they can be produced with a fully defined composition and
designed features and structures. Both poly-L-lactic acid (PLLA) and poly-DL-lactic-co-glycolic acid (PLGA) have been tested as

Table 1 Conjunctival cells grown on various biopolymer and synthetic polymer substrates (He et al., 2016)

Material Production method Cell interaction Mechanical properties

Recombinant human collagen Hydrogel Good viability Variable degradation rates

Majority of cells CK7þ (goblet)

>90%
Recombinant human collagen 2- Hydrogel Good viability Variable degradation rates
methacryloylxyethyl phosphorylcholine
Majority of cells CK7þ (goblet)
>90%
Arginine-glycine-aspartic acid (RGD)-modified Film Good viability Variable degradation rates
fibroin (Bombyx mori)
Majority of cells CK7þ (goblet)
>90%
Poly-D-lysine (PDL)-coated fibroin (B. mori) Film Good viability Variable degradation rates

Majority of cells CK7þ (goblet)

>80%
Collagen Electrospun N/A Too fragile
Poly (acrylic acid)(PAA) Electrospun Reasonable viability Control over structure and chemical
composition
Majority of cells CK7þ (goblet)
>90% Difficult to handle
Poly (caprolactone)(PCL) Electrospun Very low cell viability Control over structure and chemical
composition
Poly (vinyl alcohol) (PVA) Electrospun No cell attachment Control over structure and chemical
composition
 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology 297

potential substrates for corneal endothelial cell monolayer transplantation, as well as polyvinylidene fluoride coated with type IV
collagen. Confluent monolayers formed on PLLA and PLGA substrates and degradation could be controlled by varying the mono-
mer ratios to allow the carrier to remain intact for an interval sufficient for cells to lay down their own basement membrane (Had-
lock et al., 1999). However, current surgical treatments commonly graft an endothelial layer with a thin (< 150 mm) piece of stroma
attached to the posterior corneal surface. This stromal layer persists long term, and vision is still restored, so it is debatable as to
whether a degradable carrier is required.
The requirements for conjunctiva reconstruction differ from that of the cornea. The substitute must consist of a stable elastic
matrix, but does not necessarily need to be transparent, which allows for a wider variety of materials to be investigated. Maintaining
a mixed population of goblet and epithelial cells in a conjunctival tissue equivalent is an important consideration. It is reported that
while biopolymers such as recombinant human collagen and coated silk have variable degradation rates, their cell compatibility
and handleability was superior to that of the synthetic polymers tested (Table 1) (He et al., 2016).
PLGA/PLLA scaffolds have been evaluated for their ability to support RPE cell delivery and survival and shown to promote inte-
gration and differentiation of the cells (Tomita et al., 2005; Lavik et al., 2005). Electrospinning of PLGA-generated 3-D nanofibrous
scaffolds with mechanical properties similar to Bruch’s membrane and when coated with collagen I were able to support human
RPE cells, with a correctly orientated monolayer of cells (Warnke et al., 2013). Fibrous PLA scaffold improved retinal ganglion
cell survival and guided retinal axon orientation onto rat retinal explants in vitro (Kador et al., 2013). However, when the PLA/
PLGA scaffolds were thick (150–250 mm), they resulted in retinal detachments in rodent models and were an unsuitable scaffold
for subretinal transplantation. In addition, in some studies, degradation of PLGA/PLLA (Tomita et al., 2005; Lavik et al., 2005; Warf-
vinge et al., 2005) caused a buildup of acidic degradation products within the subretinal space leading to inflammation, fibrosis,
and cell death (Warfvinge et al., 2005; Sundback et al., 2005). PCL, which degrades more slowly than PLGA/PLLA, showed no
increase in acidity within the subretinal space (Tao et al., 2007; Grayson et al., 2004). In vitro studies showed an increase in cell
attachment and organization with a decrease in markers of early progenitors and an increase in photoreceptor markers (Steedman
et al., 2010). Thin (5–6 mm) PCL scaffolds that were highly permeable resulted in minimal physical distortion and good perme-
ability (Tao et al., 2007) and were shown to be highly compatible with the subretinal space in mice and pigs. They supported
RPE cells (Steedman et al., 2010), and porous scaffolds with 1 mm continuous pores supported a functional monolayer of fetal
human RPE cells that expressed mature markers, increased pigmentation, cell density, barrier function, polarized growth factor
secretion, and metabolite transport (McHugh et al., 2014). Improving the hydrophilicity and surface morphology of PCL scaffolds
using plasma treatments or alkaline hydrolysis increased the biocompatibility, wettability, cell adhesion, and viability of the cells
and led to a functional RPE cell layer (Shahmoradi et al., 2017). Hybrid electrospun scaffolds fabricated with PCL, silk fibroin, and
gelatin generated thin porous scaffolds that sustained a RPE morphological phenotype without signs of inflammation (Xiang et al.,
2014).
Some researchers have suggested that biostable scaffolds may be advantageous in the long term by providing support for the
transplanted cells. This is because biodegradable substrates may eventually leave the cells in direct contact with compromised
Bruch’s membrane and because the local response to degradation products may have negative effects. Biostable polymers investi-
gated include parylene, polyethylene terephthalate, and polyimide (Ilmarinen et al., 2015; Pennington and Clegg, 2016; Stanzel
et al., 2014). Surface-modified polytetrafluoroethylene (ePTFE), which is biocompatible, biostable, porous, and flexible and has
good mechanical properties for surgical handling, has also demonstrated the ability to support a functional layer of RPE cells
(Kearns et al., 2012; Krishna et al., 2011).

Conclusion

A wide range of biomaterials from decellularized tissue, biological polymers, synthetic polymers, and metals to ceramics have been
used in ophthalmic applications. The functional requirement of the biomaterial must be considered in each application and in the
eye the array of requirements is also broad, including the ability to refract the light coming into the eye, passive or active space
filling, controlling fluid flow out of the eye, electric stimulation of the neural retina or tissue regeneration. For some applications,
the use of biomaterials has been well established for many years, for example, as contact or intraocular lenses or silicone oil tam-
ponade agents to treat retinal detachments. In other applications, however, the optimal biomaterial is not yet defined, such as in
relation to tissue engineering scaffolds for subretinal RPE or corneal endothelial cell transplantation, and in these areas, further
studies are required.

References

Annaka, M., et al. (2011). Design of an injectable in situ gelation biomaterials for vitreous substitute. Biomacromolecules, 12, 4011–4021.
Antognazza, M. R., et al. (2016). Characterization of a polymer-based, fully organic prosthesis for implantation into the subretinal space of the rat. Advanced Healthcare Materials, 5,
2271–2282.
Apple, D. J., et al. (1992). Posterior capsule opacification. Survey of Ophthalmology, 37, 73–116.
Auffarth, G. U., et al. (2004). Comparison of Nd:YAG capsulotomy rates following phacoemulsification with implantation of PMMA, silicone, or acrylic intra-ocular lenses in four
European countries. Ophthalmic Epidemiology, 11, 319–329.
Baino, F. (2010). Scleral buckling biomaterials and implants for retinal detachment surgery. Medical Engineering & Physics, 32, 945–956.
298 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

Baino, F., & Potestio, I. (2016). Orbital implants: state-of-the-art review with emphasis on biomaterials and recent advances. Materials Science and Engineering: C, 69, 1410–1428.
Baino, F., & Vitale-Brovarone, C. (2015). Ceramics for oculo-orbital surgery. Ceramics International, 41, 5213–5231.
Barth, H., Crafoord, S., Andréasson, S., & Ghosh, F. (2016). A cross-linked hyaluronic acid hydrogel (Healaflow®) as a novel vitreous substitute. Graefe’s Archive for Clinical and
Experimental Ophthalmology, 254, 697–703.
Caló, E., & Khutoryanskiy, V. V. (2015). Biomedical applications of hydrogels: a review of patents and commercial products. European Polymer Journal, 65, 252–267.
Caramoy, A., et al. (2015). Development of emulsification resistant heavier-than-water tamponades using high molecular weight silicone oil polymers. Journal of Biomaterials
Applications, 30, 212–220.
Carreira, A. S., et al. (2014). New drug-eluting lenses to be applied as bandages after keratoprosthesis implantation. International Journal of Pharmaceutics, 477, 218–226.
Chan, Y. K., et al. (2011). Emulsification of silicone oil and eye movements. Investigative Ophthalmology & Visual Science, 52, 9721–9727.
Chan, Y. K., Cheung, N., Chan, W. S. C., & Wong, D. (2015). Quantifying silicone oil emulsification in patients: Are we only seeing the tip of the iceberg? Graefe’s Archive for Clinical
and Experimental Ophthalmology, 253, 1671–1675.
Chirila, T. V., Hong, Y., Dalton, P. D., Constable, I. J., & Refojo, M. F. (1998). The use of hydrophilic polymers as artificial vitreous. Progress in Polymer Science (Oxford), 23,
475–508.
Choi, H. J., et al. (2011). Efficacy of pig-to-rhesus lamellar corneal xenotransplantation. Investigative Ophthalmology & Visual Science, 52, 6643–6650.
Ciolino, J. B., et al. (2014). In vivo performance of a drug-eluting contact lens to treat glaucoma for a month. Biomaterials, 35, 432–439.
Crovace, M. C., Souza, M. T., Chinaglia, C. R., Peitl, O., & Zanotto, E. D. (2016). Biosilicate® d A multipurpose, highly bioactive glass-ceramic. In vitro, in vivo and clinical trials.
Journal of Non-Crystalline Solids, 432(Part A), 90–110.
D’Amico, D. J. (2016). Different preferences between United States and European vitreoretinal surgeons: Personal observations. Current Opinion in Ophthalmology, 27, 196–200.
Dei Cas, R., et al. (1998). Gore-Tex as an orbital implant material. Ophthalmic Plastic & Reconstructive Surgery, 14, 425–431.
Dixon, P., et al. (2015). Therapeutic contact lenses: A patent review. Expert Opinion on Therapeutic Patents, 25, 1117–1129.
Fagerholm, P., et al. (2014). Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials, 35, 2420–2427.
Friberg, T. R., & Guibord, N. M. (1999). Corneal endothelial cell loss after multiple vitreoretinal procedures and the use of silicone oil. Ophthalmic Surgery and Lasers, 30, 528–534.
Gallagher, A. G., et al. (2016). A novel peptide hydrogel for an antimicrobial bandage contact lens. Advanced Healthcare Materials, 5, 2013–2018.
Ghezzi, D., et al. (2013). A polymer optoelectronic interface restores light sensitivity in blind rat retinas. Nature Photonics, 7, 400–406.
Giordano, G. G., & Refojo, M. F. (1998). Silicone oils as vitreous substitutes. Progress in Polymer Science, 23, 509–532.
Graf, H. G., et al. (2009). High dynamic range cmos imager technologies for biomedical applications. IEEE Journal of Solid-State Circuits, 44, 281–289.
Grayson, A. C., et al. (2004). Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-
delivery microchip. Journal of Biomaterials Science. Polymer Edition, 15, 1281–1304.
de Groot, J. H., et al. (2001). Injectable intraocular lens materials based upon hydrogels. Biomacromolecules, 2, 628–634.
Guenther, E., Tröger, B., Schlosshauer, B., & Zrenner, E. (1999). Long-term survival of retinal cell cultures on retinal implant materials. Vision Research, 39, 3988–3994.
Ha, S., et al. (2016). Towards high-resolution retinal prostheses with direct optical addressing and inductive telemetry. Journal of Neural Engineering, 13. Article No. 056008.
Hadlock, T., Singh, S., Vacanti, J. P., & McLaughlin, B. J. (1999). Ocular cell monolayers cultured on biodegradable substrates. Tissue Engineering, 5, 187–196.
Hartmann, U., Sistani, F., & Steinhorst, U. H. (1999). Human and porcine anterior lens capsule as support for growing and grafting retinal pigment epithelium and iris pigment
epithelium. Graefes Archive for Clinical and Experimental Ophthalmology, 237, 940–945.
He, M., et al. (2016). Artificial polymeric scaffolds as extracellular matrix substitutes for autologous conjunctival goblet cell expansion. Investigative Ophthalmology & Visual Science,
57, 6134–6146.
Heimann, H., Stappler, T., & Wong, D. (2008). Heavy tamponade 1: A review of indications, use, and complications. Eye, 22, 1342–1359.
Ichhpujani, P., Jindal, A., & Jay Katz, L. (2009). Silicone oil induced glaucoma: A review. Graefe’s Archive for Clinical and Experimental Ophthalmology, 247, 1585–1593.
Ilmarinen, T., et al. (2015). Ultrathin polyimide membrane as cell carrier for subretinal transplantation of human embryonic stem cell derived retinal pigment epithelium. PLoS ONE,
10, e0143669.
Jordan, D. R. M. D., Gilberg, S. M. D., & Mawn, L. A. M. D. (2003). The bioceramic orbital implant: Experience With 107 Implants. Ophthalmic Plastic & Reconstructive Surgery, 19,
128–135.
de Juan, E., Spencer, R., Barale, P.-O., da Cruz, L., & Neysmith, J. (2013). Extraction of retinal tacks from subjects implanted with an epiretinal visual prosthesis. Graefe’s Archive
for Clinical and Experimental Ophthalmology, 251, 2471–2476.
Jung, S. K., Cho, W. K., Paik, J. S., & Yang, S. W. (2012). Long-term surgical outcomes of porous polyethylene orbital implants: A review of 314 cases. British Journal of
Ophthalmology, 96, 494–498.
Kador, K. E., et al. (2013). Tissue engineering the retinal ganglion cell nerve fiber layer. Biomaterials, 34, 4242–4250.
Karesh, J. W., Dresner, S. C., & Dutton, J. J. (1994). High-density porous polyethylene (Medpor) as a successful anophthalmic socket implant. Ophthalmology, 101, 1688–1696.
Karwatowski, W. S., et al. (1995). Preparation of Bruch’s membrane and analysis of the age-related changes in the structural collagens. The British Journal of Ophthalmology, 79,
944–952.
Kearns, V., et al. (2012). Plasma polymer coatings to aid retinal pigment epithelial growth for transplantation in the treatment of age related macular degeneration. Journal of
Materials Science. Materials in Medicine, 23, 2013–2021.
Khan, M. A. M. D., Brady, C. J. M. D., & Kaiser, R. S. M. D. (2015). Clinical management of proliferative vitreoretinopathy: An update. Retina, 35, 165–175.
Kimbrel, E. A., & Lanza, R. (2015). Current status of pluripotent stem cells: Moving the first therapies to the clinic. Nature Reviews. Drug Discovery, 14, 681–692.
Kirchhof, S., Goepferich, A. M., & Brandl, F. P. (2015). Hydrogels in ophthalmic applications. European Journal of Pharmaceutics and Biopharmaceutics, 95(Part B), 227–238.
Klassen, H. J., et al. (2004). Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Investigative
Ophthalmology & Visual Science, 45, 4167–4173.
Kleinberg, T. T., Tzekov, R. T., Stein, L., Ravi, N., & Kaushal, S. (2011). Vitreous substitutes: A comprehensive review. Survey of Ophthalmology, 56, 300–323.
Klinge, P. M., et al. (2001). Immunohistochemical characterization of axonal sprouting and reactive tissue changes after long-term implantation of a polyimide sieve electrode to the
transected adult rat sciatic nerve. Biomaterials, 22, 2333–2343.
Koopmans, S. A., Terwee, T., Barkhof, J., Haitjema, H. J., & Kooijman, A. C. (2003). Polymer refilling of presbyopic human lenses in vitro restores the ability to undergo
accommodative changes. Investigative Ophthalmology & Visual Science, 44, 250–257.
Koopmans, S. A., Terwee, T., & van Kooten, T. G. (2011). Prevention of capsular opacification after accommodative lens refilling surgery in rabbits. Biomaterials, 32, 5743–5755.
van Kooten, T. G., et al. (2006). Development of an accommodating intra-ocular lensdIn vitro prevention of re-growth of pig and rabbit lens capsule epithelial cells. Biomaterials,
27, 5554–5560.
Krishna, Y., et al. (2011). Expanded polytetrafluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration. British
Journal of Ophthalmology, 95, 569–573.
Lavik, E. B., Klassen, H., Warfvinge, K., Langer, R., & Young, M. J. (2005). Fabrication of degradable polymer scaffolds to direct the integration and differentiation of retinal
progenitors. Biomaterials, 26, 3187–3196. http://www.sciencedirect.com/science/article/pii/S0142961204007719.
Lee, H. I., et al. (2007). The efficacy of an acrylic intraocular lens surface modified with polyethylene glycol in posterior capsular opacification. Journal of Korean Medical Science,
22, 502–507.
Levis, H. J., Brown, R. A., & Daniels, J. T. (2010). Plastic compressed collagen as a biomimetic substrate for human limbal epithelial cell culture. Biomaterials, 31, 7726–7737.
http://www.sciencedirect.com/science/article/B7726TWB-7750NH7708G-7727/7722/64200e64278cfc64207b64206da64278af64205c64200a64205a64206c64702d.
 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology 299

Levis, H. J., Massie, I., Dziasko, M. A., Kaasi, A., & Daniels, J. T. (2013). Rapid tissue engineering of biomimetic human corneal limbal crypts with 3D niche architecture.
Biomaterials, 34, 8860–8868.
Liang, C., et al. (1998). An evaluation of methylated collagen as a substitute for vitreous and aqueous humor. International Ophthalmology, 22, 13–18.
Light, D. J. (2006). Silicone oil emulsification in the anterior chamber after vitreoretinal surgery. OptometrydJournal of the American Optometric Association, 77, 446–449.
Lin, X. M. D. P., et al. (2012). Preliminary efficacy and safety of a silicone oil-filled foldable capsular vitreous body in the treatment of severe retinal detachment. Retina, 32,
729–741.
Liu, W., et al. (2008). Recombinant human collagen for tissue engineered corneal substitutes. Biomaterials, 29, 1147–1158.
Liu, Y. C., Wong, T. T., & Mehta, J. S. (2013). Intraocular lens as a drug delivery reservoir. Current Opinion in Ophthalmology, 24, 53–59.
Ma, X., Schou, K. R., Maloney-Schou, M., Harwin, F. M., & Ng, J. D. (2011). The porous polyethylene/bioglass spherical orbital implant: A retrospective study of 170 cases.
Ophthalmic Plastic & Reconstructive Surgery January/February, 27, 21–27.
MacLaren, R. E., et al. (2006). Retinal repair by transplantation of photoreceptor precursors. Nature, 444, 203–207. https://doi.org/210.1038/nature05161.
Maghami, M. H., Sodagar, A. M., Lashay, A., Riazi-Esfahani, H., & Riazi-Esfahani, M. (2014). Visual prostheses: The enabling technology to give sight to the blind. Journal of
Ophthalmic and Vision Research, 9, 494–505.
Malafaya, P. B., Silva, G. A., & Reis, R. L. (2007). Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Advanced
Drug Delivery Reviews, 59, 207–233.
Manasses, D. T., & Au, L. (2016). The new era of glaucoma micro-stent surgery. Ophthalmology and Therapy, 5, 135–146.
Maulvi, F. A., Soni, T. G., & Shah, D. O. (2016). A review on therapeutic contact lenses for ocular drug delivery. Drug Delivery, 23, 3017–3026.
Mawn, L. A., Jordan, D. R., & Gilberg, S. (1998). Scanning electron microscopic examination of porous orbital implants. Canadian Journal of Ophthalmology, 33, 203–209.
McHugh, K. J., Tao, S. L., & Saint-Geniez, M. (2014). Porous poly(epsilon-caprolactone) scaffolds for retinal pigment epithelium transplantation. Investigative Ophthalmology &
Visual Science, 55, 1754–1762.
Morphis, G., et al. (2012). Retrospective review of 50 eyes with long-term silicone oil tamponade for more than 12 months. Graefe’s Archive for Clinical and Experimental
Ophthalmology, 250, 645–652.
Okumura, N., et al. (2012). ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. The American Journal of Pathology,
181, 268–277.
Ozdek, S., Yuksel, N., Gurelik, G., & Hasanreisoglu, B. (2011). High-density silicone oil as an intraocular tamponade in complex retinal detachments. Canadian Journal of
Ophthalmology/Journal Canadien d’Ophtalmologie, 46, 51–55.
Pastor, J. C., Zarco, J. M., Del Nozal, M. J., Pampliega, A., & Marinero, P. (1998). Clinical consequences of the use of highly purified silicone oil: Comparative study of highly and
less purified silicone oil. European Journal of Ophthalmology, 8, 179–183.
Patel, M., et al. (2010). Cyclic acetal hydroxyapatite nanocomposites for orbital bone regeneration. Tissue Engineering – Part A, 16, 55–65.
Pellegrini, G., et al. (2016). From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU. Regenerative Medicine, 11, 407–420.
Pennington, B. O., & Clegg, D. O. (2016). Pluripotent stem cell-based therapies in combination with substrate for the treatment of age-related macular degeneration. Journal of
Ocular Pharmacology and Therapeutics.
Pinchuk, L., et al. (2017). The development of a micro-shunt made from poly(styrene-block-isobutylene-block-styrene) to treat glaucoma. Journal of Biomedical Materials Research.
Part B, Applied Biomaterials, 105, 211–221.
De Potter, P., Shields, C. L., Shields, J. A., & Singh, A. D. (1994). Use of the hydroxyapatite ocular implant in the pediatric population. Archives of Ophthalmology, 112, 208–212.
Pruett, R. C., Schepens, C. L., & Swann, D. A. (1979). Hyaluronic acid vitreous substitute: A six-year clinical evaluation. Archives of Ophthalmology, 97, 2325–2330.
Rahman, I., Said, D. G., Maharajan, V. S., & Dua, H. S. (2009). Amniotic membrane in ophthalmology: Indications and limitations. Eye (Lond), 23, 1954–1961.
Refojo, M. F. (1996). Ophthalmic applications. In B. D. Ratner, A. S. Hoffman, F. J. Schoen, & J. E. Lemons (Eds.), Biomaterials science: An introduction to materials in medicine.
United States of America: Academic Press.
Richardson, R. R., Jr., Miller, J. A., & Reichert, W. M. (1993). Polyimides as biomaterials: Preliminary biocompatibility testing. Biomaterials, 14, 627–635.
Rønbeck, M., & Kugelberg, M. (2014). Posterior capsule opacification with 3 intraocular lenses: 12-year prospective study. Journal of Cataract & Refractive Surgery, 40, 70–76.
Sami, D., Young, S., & Petersen, R. (2007). Perspective on orbital enucleation implants. Survey of Ophthalmology, 52, 244–265.
Santhanam, S., Liang, J., Struckhoff, J., Hamilton, P. D., & Ravi, N. (2016). Biomimetic hydrogel with tunable mechanical properties for vitreous substitutes. Acta Biomaterialia, 43,
327–337.
Schellini, S., El Dib, R., Silva, L. R. E., Farat, J. G., Zhang, Y., & Jorge, E. C. (2016). Integrated versus non-integrated orbital implants for treating anophthalmic sockets. Cochrane
Database of Systematic Reviews, 11. https://doi.org/10.1002/14651858.CD010293.pub2. Article No. CD010293.
Schepens, C. L., & Acosta, F. (1991). Scleral implants: An historical perspective. Survey of Ophthalmology, 35, 447–453.
Schramm, C., et al. (2012). The cross-linked biopolymer hyaluronic acid as an artificial vitreous substitute. Investigative Ophthalmology & Visual Science, 53, 613–621.
Scott, I. U., et al. (2005). Outcomes of complex retinal detachment repair using 1000- vs 5000-centistoke silicone oil. Archives of Ophthalmology, 123, 473–478.
Sebag, J. (1992). Anatomy and pathology of the vitreo-retinal interface. Eye, 6, 541–552.
Sebag, J. (1998). Macromolecular structure of the corpus vitreus. Progress in Polymer Science, 23, 415–446.
Second Sight Medical Products (2013) Argus II Retinal Prosthesis System Surgeon Manual. Document number: 09001-004. Second Sight, Sylmar.
Seo, J.-M., et al. (2004). Biocompatibility of polyimide microelectrode array for retinal stimulation. Materials Science and Engineering: C, 24, 185–189.
Shahmoradi, S., et al. (2017). Controlled surface morphology and hydrophilicity of polycaprolactone toward human retinal pigment epithelium cells. Materials Science and
Engineering: C, 73, 300–309.
Son, J., Kim, C.-S., & Yang, J. (2012). Comparison of experimental porous silicone implants and porous silicone implants. Graefe’s Archive for Clinical and Experimental
Ophthalmology, 250, 879–885.
Stanzel, B. V., et al. (2014). Human RPE stem cells grown into polarized RPE monolayers on a polyester matrix are maintained after grafting into rabbit subretinal space. Stem Cell
Reports, 2, 64–77.
Steedman, M. R., Tao, S. L., Klassen, H., & Desai, T. A. (2010). Enhanced differentiation of retinal progenitor cells using microfabricated topographical cues. Biomedical
Microdevices, 12, 363–369.
Su, X., et al. (2015). Recent progress in using biomaterials as vitreous substitutes. Biomacromolecules, 16, 3093–3102.
Sundback, C. A., et al. (2005). Biocompatibility analysis of poly(glycerol sebacate) as a nerve guide material. Biomaterials, 26, 5454–5464. http://www.sciencedirect.com/science/
article/pii/S0142961205001547.
Suter, A. J., Molteno, A. C. B., Bevin, T. H., Fulton, J. D., & Herbison, P. (2002). Long term follow up of bone derived hydroxyapatite orbital implants. British Journal of
Ophthalmology, 86, 1287–1292.
Swindle-Reilly, K. E., Reilly, M. A., & Ravi, N. (2016). Biomaterials and Regenerative Medicine in Ophthalmology (Second Edition) (pp. 101–130). Duxford, UK: Woodhead
Publishing.
Tang, Z. L., Akiyama, Y., & Okano, T. (2012). Temperature-responsive polymer modified surface for cell sheet engineering. Polymers, 4, 1478–1498.
Tao, S., et al. (2007). Survival, migration and differentiation of retinal progenitor cells transplanted on micro-machined poly(methyl methacrylate) scaffolds to the subretinal space.
Lab on a Chip, 7, 695. http://pubs.rsc.org.ezproxy.liv.ac.uk/en/Content/ArticleLanding/2007/LC/b618583e.
Thomas, M., Shorter, E., Joslin, C. E., McMahon, T. J., & Cortina, M. S. (2015). Contact lens use in patients with Boston keratoprosthesis type 1: Fitting, management, and
complications. Eye and Contact Lens, 41, 334–340.
300 Biomaterials: Biomaterial applications and advanced medical technologies j Biomaterials in Ophthalmology

Thumann, G., Schraermeyer, U., Bartz-Schmidt, K. U., & Heimann, K. (1997). Descemet’s membrane as membranous support in RPE/IPE transplantation. Current Eye Research, 16,
1236–1238.
Tomita, M., et al. (2005). Biodegradable polymer composite grafts promote the survival and differentiation of retinal progenitor cells. Stem Cells, 23, 1579–1588. http://onlinelibrary.
wiley.com/doi/1510.1634/stemcells.2005-0111/abstract.
Turowski, P., et al. (2004). Basement membrane-dependent modification of phenotype and gene expression in human retinal pigment epithelial ARPE-19 cells. Investigative
Ophthalmology & Visual Science, 45, 2786–2794.
Warfvinge, K., et al. (2005). Retinal progenitor cell xenografts to the pig retina: Morphologic integration and cytochemical differentiation. Archives of Ophthalmology, 123, 1385–
1393. http://archopht.ama-assn.org/cgi/content/abstract/1123/1310/1385.
Warnke, P. H., et al. (2013). Primordium of an artificial Bruch’s membrane made of nanofibers for engineering of retinal pigment epithelium cell monolayers. Acta Biomaterialia, 9,
9414–9422.
Wickham, L., Tranos, P., Hiscott, P., & Charteris, D. (2010). The use of silicone oil-RMN3 (Oxane HD) as heavier-than-water internal tamponade in complicated inferior retinal
detachment surgery. Graefe’s Archive for Clinical and Experimental Ophthalmology, 248, 1225–1231.
Williams, R. L. P., Day, M. P., Garvey, M. J. P., English, R. P., & Wong, D. F. (2010). Increasing the extensional viscosity of silicone oil reduces the tendency for emulsification.
Retina, 30, 300–304.
Williams, R. L., et al. (2011). Injectability of silicone oil-based tamponade agents. British Journal of Ophthalmology, 95, 273–276.
Wong, D., & Williams, R. (2005). In B. Kirchhof, & D. Wong (Eds.), Vitreo-retinal surgery (pp. 147–161). Berlin, Heidelberg: Springer Berlin Heidelberg.
Xiang, P., et al. (2014). A novel Bruch’s membrane-mimetic electrospun substrate scaffold for human retinal pigment epithelium cells. Biomaterials, 35, 9777–9788.
Xinming, L., et al. (2008). Polymeric hydrogels for novel contact lens-based ophthalmic drug delivery systems: A review. Contact Lens and Anterior Eye, 31, 57–64.
Yaji, N., Yamato, M., Yang, J., Okano, T., & Hori, S. (2009). Transplantation of tissue-engineered retinal pigment epithelial cell sheets in a rabbit model. Biomaterials, 30, 797–803.
Yang, H., Wang, R., Gu, Q., & Zhang, X. (2008). Feasibility study of chitosan as intravitreous tamponade material. Graefe’s Archive for Clinical and Experimental Ophthalmology,
246, 1097–1105.
Yang, W., et al. (2014). Preliminary study on retinal vascular and oxygen-related changes after long-term silicone oil and foldable capsular vitreous body tamponade. Scientific
Reports, 4, 5272.
Yuen, C., Williams, R., Batterbury, M., & Grierson, I. (2006). Modification of the surface properties of a lens material to influence posterior capsular opacification. Clinical &
Experimental Ophthalmology, 34, 568–574.