materials

Review
Contact Lens Materials: A Materials
Science Perspective
Christopher Stephen Andrew Musgrave 1 and Fengzhou Fang 1,2, *
1 Centre of MicroNano Manufacturing Technology (MNMT-Dublin), University College Dublin,
D14 YH57 Dublin, Ireland; christopher.musgrave@ucd.ie
2 State Key Laboratory of Precision Measuring Technology and Instruments, Centre of MicroNano
Manufacturing Technology (MNMT), Tianjin University, Tianjin 300072, China
* Correspondence: fengzhou.fang@ucd.ie; Tel.: +353-1-716-1810




Received: 20 December 2018; Accepted: 7 January 2019; Published: 14 January 2019


Abstract: More is demanded from ophthalmic treatments using contact lenses, which are currently
used by over 125 million people around the world. Improving the material of contact lenses (CLs)
is a now rapidly evolving discipline. These materials are developing alongside the advances made
in related biomaterials for applications such as drug delivery. Contact lens materials are typically
based on polymer- or silicone-hydrogel, with additional manufacturing technologies employed to
produce the final lens. These processes are simply not enough to meet the increasing demands from
CLs and the ever-increasing number of contact lens (CL) users. This review provides an advanced
perspective on contact lens materials, with an emphasis on materials science employed in developing
new CLs. The future trends for CL materials are to graft, incapsulate, or modify the classic CL
material structure to provide new or improved functionality. In this paper, we discuss some of the
fundamental material properties, present an outlook from related emerging biomaterials, and provide
viewpoints of precision manufacturing in CL development.

Keywords: contact lens; materials; biomedical implant

1. Introduction
The market for contact lenses (CLs) is ever-growing, with over 125 million consumers as of 2004 [1],
and an estimated global market size worth $7.1 billion in 2015 [2]. A quick search of patent literature
shows that over 100 patents have been filed since 2000, representing the growing popularity of CLs.
The applications of CLs range from corrective vision and therapeutics to cosmetic appearance [3,4].
Within these applications comes the demands from the end user of the lenses, including length of wear,
comfort, durability, practically of handling, stability of vision, etc. This also means that within the
applications of contact lenses comes the demands from manufacturers, such as material costs, ease of
production, and reliability of the CLs, etc. Finally, the demands from manufacturers determine the
parameters of the material which scientists must focus their research on for developing CL materials.
This premise has guided materials scientists, from the creation of glass scleral lenses in the 1930s to
rigid, non-gas-permeable polymethyl methacrylate (PMMA) in the 1940s. The 1960s and 70s ushered
in hydrogel (polymer and silicone) lenses, with silicone hydrogel proving to be the most dominant
kind of CL material today.
Commonly, the labels of “hard” or “soft” are used as blanket definitions of CLs [3,4]. Hard
CLs are rigid (durable), gas-permeable lenses, whereas soft contact lenses are made of flexible,
high-water-content material. Hard lenses are often interchangeably referred to as rigid gas-permeable
lenses (RGPs); however, this is not strictly true. The first PMMA lenses could be classified as hard,
whereas modern RGP lenses are, in fact, more flexible, due to the incorporation of low-modulus

Materials 2019, 12, 261; doi:10.3390/ma12020261 www.mdpi.com/journal/materials

Materials 2019, 12, 261 2 of 35

Materials 2019, 12, x FOR PEER REVIEW 2 of 36

components—hence, they are more rigid, rather than hard. Another defining characteristic is that
PMMA hard lenses
characteristic is thathave
PMMA no oxygen permeability,
hard lenses have nowhereas
oxygenRGP lenses are whereas
permeability, permeable. RGPOnlenses
the other
are
hand, a softOn
permeable. contact lens (SCL)
the other hand, is a highly
a soft flexible,
contact oxygen-permeable
lens (SCL) material
is a highly flexible, with often high
oxygen-permeable
water-content.
material with often Thishigh
flexibility means that
water-content. ThisSCLs fit themeans
flexibility shapethat
of aSCLs
user’s eyeshape
fit the muchoffaster than
a user’s eyea
rigid lens. SCLs can be disposed daily, weekly, or monthly. These blanket definitions
much faster than a rigid lens. SCLs can be disposed daily, weekly, or monthly. These blanket of CLs can hint at
its material of
definitions properties,
CLs can though
hint at notits for certain.
material There is often
properties, an overlap
though not for in materials
certain. Thereused
is between
often an
hard
in materials used between hard and soft lenses, such as silicone hydrogels and RGPs. materials,
and soft lenses, such as silicone hydrogels and RGPs. Although both use silicone Although
the
use difference lies in factors
silicone materials, such as the
the difference liesgel
in network and as
factors such water
the content.
gel network Derivatives
and water therein can
content.
further diversify the range of possible CLs and their properties. The requirements
Derivatives therein can further diversify the range of possible CLs and their properties. The for CLs are quite
extensive,
requirementsand for
there
CLsareare
a huge
quitenumber of existing
extensive, CLs on
and there arethe market
a huge to reflect
number of this; daily-disposable
existing CLs on the
lenses, weekly/monthly
to reflect lenses,lenses,
this; daily-disposable special fitting lenses, and
weekly/monthly even
lenses, lensesfitting
special that can be worn
lenses, overnight.
and even lenses
Users’ demands can be described by several general parameters, such as comfort,
that can be worn overnight. Users’ demands can be described by several general parameters, wear time, handling
such
(cleaning, ease of use), cost, and vision specifications (Figure 1) [3,4].
comfort, wear time, handling (cleaning, ease of use), cost, and vision specifications (Figure 1) [3,4].

Figure 1. General user demands from CLs. Each parameter can be sub-divided into many categories,
which is
which is why
why the
the CL
CL market
market is
is so
so vastly
vastly populated.
populated.

PMMA isisa durable,

a durable, optically transparent
optically polymer
transparent with limited
polymer with hydrophilic character. character.
limited hydrophilic However,
PMMA
However, hasPMMA
negligible oxygen permeability,
has negligible which may
oxygen permeability, lead may
which to several
lead toeye health
several eyeissues,
healthsuch as
issues,
hypoxia
such as [5,6]. Researchers
hypoxia quickly discovered
[5,6]. Researchers quicklypolymer hydrogels,
discovered polymer which were typically
hydrogels, which based
were ontypically
hydroxy
ethyl
basedmethacrylate
on hydroxy (HEMA) [7,8]. These (HEMA)
ethyl methacrylate polymer hydrogels
[7,8]. These were composed
polymer of hydrophilic
hydrogels monomers,
were composed of
meaning
hydrophilictheymonomers,
contained electrochemical polarity allowing
meaning they contained interaction
electrochemical with water.
polarity Thisinteraction
allowing provided muchwith
greater biocompatibility
water. This provided much than greater
PMMA.biocompatibility
These hydrogelsthan werePMMA.
also an oxygen-permeable
These hydrogels were and also
flexible
an
class of material thatand
oxygen-permeable could hold aclass
flexible largeofpercentage
material thatof water
couldwithin
hold athe polymer
large network.
percentage These factors
of water within
improved
the polymer the network.
comfort, oxygen
These permeability,
factors improved and wear time of CLs,
the comfort, whichpermeability,
oxygen resulted in many
andCL derivatives
wear time of
based on HEMA
CLs, which resulted[9,10]. Progress
in many CL did not stop,based
derivatives as theon oxygen
HEMA permeability of HEMA
[9,10]. Progress did not hydrogels
stop, aswas
the
not sufficient
oxygen for extended
permeability of HEMACL wear (>24 h)was
hydrogels [3,4].not
The next evolution
sufficient of CLsCL
for extended was silicone-based
wear (>24 h) [3,4].rigid
The
lenses and hydrogels.
next evolution of CLs These materials haverigid
was silicone-based verylenses
high gas-permeability,
and hydrogels. These meaning extended-wear
materials have verylenses
high
could be fabricated.
gas-permeability, However,
meaning silicone materials
extended-wear lensesare inherently
could hydrophobic,
be fabricated. However,meaning
siliconethey are not
materials
comfortable
are inherently due to factors such
hydrophobic, as poorthey
meaning wetting andcomfortable
are not abrasiveness. duePolymer scientists
to factors such asovercame
poor wettingthis
by
andusing copolymerization
abrasiveness. Polymer of ascientists
silicone monomer
overcame(e.g., thissiloxymethacrylates and fluoromethacrylates)
by using copolymerization of a silicone
with hydrophilic
monomer comonomers to addand
(e.g., siloxymethacrylates the fluoromethacrylates)
desired hydrophilic character [11–14]. This
with hydrophilic was particularly
comonomers to add
successful
the desiredforhydrophilic
silicone hydrogel
characterlenses, whichThis
[11–14]. is the most
was dominant successful
particularly CL materialfor onsilicone
the market today
hydrogel
(64%
lenses,inwhich
the US) [15].most
is the Newer CL materials
dominant CL materialappeared
on theinmarket
the 1990s,
todaysuch(64%asin
polyvinyl alcohol
the US) [15]. (PVA),
Newer CL
which is a appeared
materials low-cost and very1990s,
in the hydrophilic
such aspolymer
polyvinyl [16,17]. In fact,
alcohol the which
(PVA), PVA hydrogel was the
is a low-cost subject
and very
of investigation
hydrophilic in the[16,17].
polymer early 1990s as athe
In fact, potential CL material
PVA hydrogel [18].subject
was the In addition, new surface
of investigation in coatings,
the early
1990s as a potential CL material [18]. In addition, new surface coatings, such as polyethylene glycol
(PEG) have appeared in recent years to improve the hydrophilicity of silicone-based CLs [19]. These
are just two examples amongst a vast pool of relevant literature.
Materials 2019, 12, 261 3 of 35

such as polyethylene glycol (PEG) have appeared in recent years to improve the hydrophilicity of
silicone-based CLs [19]. These are just two examples amongst a vast pool of relevant literature.
Despite this significant progress, more is demanded from CLs today. CLs provide a route for
improving the quality of life. This could simply be for cosmetic reasons or for corrective vision in place
of traditional spectacles, which remain the two most common uses of CLs today [20]. Cosmetic CLs
can include anything from pigmented to prosthetic CLs. However, CLs are increasingly considered
a platform for more proactive ophthalmic treatments. As the number of people developing myopia,
glaucoma, and other eye conditions is increasing globally, more effective treatments are required [21].
One review paper estimated that over 1400 million people worldwide are currently suffering from
myopia [22]. Myopia control using CLs has been a subject of debate [23]; however, there is mounting
research that specialty lenses can control the progression of myopia [24]. CLs can offer one such
treatment route for glaucoma; the drug-loaded lens can simply be placed onto the eye, and the drug is
released onto the eye [25–27]. This is currently a hot topic, and has been the subject of several excellent
review papers [27–29]. Therefore, it is clear that new and improved CL materials are required to deliver
more effective treatments for these growing issues.
Many sources detail the general synthesis of hydrogels or discuss their end application, such as
bioavailability, eye-fitting, CLs in practice, manufacturing, and much more [3,4,30,31]. There have been
some articles that have talked specifically about materials for contact lenses, which provided important
insights at the time [32,33]. Other sources have discussed general bioavailable materials [34,35] and
the properties of CL brands [33], with a lot of modern research being concerned about drug delivery
using CLs [27,36–38]. This review brings together research specifically about the latest development of
CL materials, and touches on details from a materials science perspective. We aim to bring together
the innovations in CL materials and explain the impact they have. We discuss general polymerization
mechanisms and monomers used to produce CL materials, which are all considerations for designing
new CLs. We then discuss new evolutions to the main classes of CL materials, such as RGP lenses,
HEMA- and silicone-hydrogels, and their future perspectives. Finally, we highlight some particularly
impactful materials, emerging materials’ technologies, and future manufacturing viewpoints.

2. Contact Lens Materials

2.1. Overview
To manufacture CLs, there must be a suitable polymeric material. This opens an incredible number
of possibilities, not only from the range of polymers but to the formula of components within a given
recipe. In addition, there can be considerations for the different types of polymerization mechanisms to
form the same polymer, such as radical vs. catalytic polymerizations and derivatives. Within this, the
polymerization conditions (temperature, initiator type, vessel used, etc.) can be altered to produce the
same polymer but with different properties. Finally, the material must be suitable for the manufacturing
stages, which include the synthesis, inspection, and packaging processes. The manufacturing stages
have their own intricacies, which will be discussed later; thus, it is easy to quickly get lost in the search
for the most suitable CL material. The extent of variation in materials is why there is such a wide range
of CLs available today, and this has been extensively researched. Figure 2 contains some of the most
important factors from a materials science perspective when designing CLs. From this, an assessment
of current CL materials’ pros and cons is given in Table 1.
Materials 2019, 12, x FOR PEER REVIEW 4 of 36
Materials 2019, 12, 261 4 of 35

Table 1. General pros and cons of current CL material classes.

CL Material Table 1. General

Pros pros and cons of current CL material classes. Cons
PMMA Inexpensive, well-understood polymer No oxygen permeability, inflexible on the eye
CL Material Pros Cons
Expensive regents, requires hydrophilic
RGPPMMA High oxygen permeability,
Inexpensive, durable
well-understood polymer No oxygen permeability, inflexible on the eye
comonomer, canregents,
Expensive be abrasive
requires hydrophilic
HEMARGP Inexpensive, High oxygen permeability,
biocompatible, durable
abundant Low oxygen permeability, protein deposition
comonomer, can be abrasive
hydrogel Inexpensive,
copolymer biocompatible, abundant
possibilities issues Low oxygen permeability, protein
HEMA hydrogel
copolymer possibilities deposition issues
Silicone High oxygen permeability, durable, Expensive regents, requires hydrophilic
Expensive regents, requires hydrophilic
Silicone hydrogel
hydrogel High oxygen permeability, durable, comfortable
comfortable comonomer, can be
comonomer, canabrasive
be abrasive
PVA Inexpensive, straight-forward
Inexpensive, straight-forward manufacturing,
Low oxygen permeability, fixedwater
water content
PVA biocompatible Low oxygen permeability, fixed content
manufacturing, biocompatible

dependent on many parameters

Figure 2. A CL lens is dependent parameters from aa material
material science
science perspective.
perspective. Stronger
emphasis onon specific
specificcharacteristics
characteristicsare
arerequired,
required,depending
depending onon
thethe specific
specific demand
demand placed
placed on CL.
on the the
CL. final
The The CL
final CL material
material accountsaccounts
for wear for
timewear time andThese
and comfort. comfort. These characteristics
characteristics are often
are often dependent on
dependent
the on but
materials, the also
materials, butmanufacturing
includes also includes manufacturing
processes, suchprocesses,
as plasmasuch as plasma treatment.
treatment.

For clarity,
clarity,a apolymer
polymer is aislarge macromolecule
a large macromoleculecomposed of hundreds
composed or thousands
of hundreds of a repeating
or thousands of a
molecule,
repeating called a monomer.
molecule, Each monomer
called a monomer. Each has a covalent
monomer has bond between
a covalent bondeach connecting
between unit. Some
each connecting
common
unit. Some monomers
common and polymers
monomers andused in the production
polymers used in the of CLs can be
production ofseen
CLs incanFigure 3. The
be seen process
in Figure 3.
by which the polymer is formed is called polymerization. Another reactive
The process by which the polymer is formed is called polymerization. Another reactive molecule, molecule, the initiator,
is
theused to begin
initiator, the polymerization.
is used Polymerization
to begin the polymerization. initiators are typically
Polymerization initiators selected basedselected
are typically on the
interaction
based on the with the reactive
interaction with functional groups
the reactive within groups
functional the monomers.
within the Radicals are formed
monomers. Radicalson the
are
breakdown of the initiator, which then induce the polymerization by
formed on the breakdown of the initiator, which then induce the polymerization by stripping astripping a radical from the
monomer
radical from functional
the monomergroup. functional
Now the monomer
group. Now has athe
free radical within
monomer has a itself, which reacts
free radical withinwith a
itself,
neighboring monomer functional group by stripping a radical from this group.
which reacts with a neighboring monomer functional group by stripping a radical from this group. The original monomer
would have then
The original formed
monomer a newhave
would bondthen
withformed
the new a monomer
new bondunit, withwhich
the new now has a new
monomer radical
unit, whichto
continue
now has polymerizing.
a new radical to This propagation
continue step is continuously
polymerizing. repeated,
This propagation step thus forming therepeated,
is continuously polymer
over
thus time,
forming whichthe extinguishes
polymer over when
time,there
whichare extinguishes
no more monomerswhen thereto consume.
are no Themorepolymerization
monomers to
terminates
consume. The when the radical isterminates
polymerization quenched when
in another manner,
the radical such as by
is quenched in aanother
radicalmanner,
scavenger. suchThe
as
initiator can scavenger.
by a radical be chosen for Thetheir practicality,
initiator can be such
chosenas for
ultra-violet (UV) or thermal
their practicality, such asinitiators, which
ultra-violet (UV)isor
a
huge consideration for the manufacturing method in producing CLs.
thermal initiators, which is a huge consideration for the manufacturing method in producing CLs.
Materials 2019, 12, 261 5 of 35
Materials 2019, 12, x FOR PEER REVIEW 5 of 36

Figure 3.
3. The
Thechemical
chemicalstructures of of
structures common
common monomers andand
monomers polymers usedused
polymers to produce CLs. This
to produce CLs.
includes somesome
This includes macromonomers
macromonomers andandcross-linking agents.
cross-linking agents.PMMA—poly
PMMA—polymethyl
methyl methacrylate,
methacrylate,
PVA—poly vinyl
PVA—poly alcohol,
vinyl PEG—poly
alcohol, ethylene glycol,
PEG—poly DMA—dimethyl
ethylene methacrylate, HEMA—hydroxy
glycol, DMA—dimethyl methacrylate,
ethyl methacrylate,
HEMA—hydroxy NVP—N-vinyl
ethyl methacrylate,pyrrolidone,
NVP—N-vinyl EGDMA—ethylene glycol dimethacrylate,
pyrrolidone, EGDMA—ethylene glycol
PDMS—poly dimethyl
dimethacrylate, siloxane, TRIS—3-[tris(trimethylsiloxy)silyl]propyl
PDMS—poly methacrylate.
dimethyl siloxane, TRIS—3-[tris(trimethylsiloxy)silyl]propyl
methacrylate.
2.2. Polymerization Mechanisms
2.2. Polymerization Mechanisms (FRP) is a type of chain-growth polymerization mechanism. Typically,
Free-radical polymerization
free-radical polymerizations
Free-radical polymerization are often not easily
(FRP) is a controlled, producing high
type of chain-growth dispersity (large
polymerization variations
mechanism.
in molecular
Typically, weights) polymerizations
free-radical of the resulting polymers.
are often not This can controlled,
easily lead to a distribution
producing high of thedispersity
polymer
properties. High strain and tensile modulus polymers are often determined
(large variations in molecular weights) of the resulting polymers. This can lead to a distribution by the length of the
of
polymer chains [39]. One advantage of FRP is that it is easy to form
the polymer properties. High strain and tensile modulus polymers are often determined by the gelling networks with, as the
polymerization
length has many
of the polymer chainsinitiation sitesadvantage
[39]. One within theofvessel.
FRP isThis
thatallows for to
it is easy theform
simultaneous growth
gelling networks
of many chains which can physically entangle or cross-link to form
with, as the polymerization has many initiation sites within the vessel. This allows for the the gel network. Cross-linking
is dependent on
simultaneous one of
growth of the
many monomers containing
chains which two functional
can physically entangle groups, which enables
or cross-link to formchemical
the gel
bonding to two different polymer chains. Cross-linking polymer
network. Cross-linking is dependent on one of the monomers containing two functional groups, chains often improves gelling
and increases the modulus of the material. To date, most CLs
which enables chemical bonding to two different polymer chains. Cross-linking polymer chainsare produced using free-radical
polymerization
often [11,13,40–44].
improves gelling It is facile
and increases the and doesn’t
modulus require
of the expensive
material. To date,reagents,
most CLssuch areasproduced
catalysts.
Furthermore, unwanted/unreacted chemicals can be removed from the material
using free-radical polymerization [11,13,40–44]. It is facile and doesn’t require expensive reagents, on post-fabrication
cleaning
such processes.
as catalysts. Catalysts are
Furthermore, often composed of chemicals
unwanted/unreacted heavy metals,can be which
removed is something
from the to avoid for
material on
human health.
post-fabrication cleaning processes. Catalysts are often composed of heavy metals, which is
Today,tomost
something avoidCLs are produced
for human health. from a polymerization of two or more monomers [42,45].
Copolymers
Today, incorporate
most CLs are the produced
properties from
of the aindividual polymers;
polymerization of consequently,
two or more copolymerization
monomers [42,45]. is
often the first method used in overcoming issues with a single polymer.
Copolymers incorporate the properties of the individual polymers; consequently, copolymerization This principle has governed
theoften
is development of CLs for
the first method usedmany years. For example,
in overcoming issues with silicone polymers
a single polymer. are This
very principle
hydrophobic,has
despite their high oxygen permeability. Therefore, they are not ideal
governed the development of CLs for many years. For example, silicone polymers are very as a homopolymer CL material.
However, copolymers
hydrophobic, despiteoftheirsilicones
highwith a hydrophilic
oxygen (highly Therefore,
permeability. polar) monomer they canaresolve
not this problem.
ideal as a
Copolymerization may also be used to enhance physical properties
homopolymer CL material. However, copolymers of silicones with a hydrophilic (highly polar) through the cross-linking of
polymer chains by adding molecular weight to the chain. In some
monomer can solve this problem. Copolymerization may also be used to enhance physical cases, adding a soft polymer can
reduce the through
properties modulusthe of cross-linking
particularly tough materials
of polymer chains(often silicone-based
by adding molecular materials).
weight toHydrophobic
the chain. In
comonomers add oxygen permeability to materials that require improvement
some cases, adding a soft polymer can reduce the modulus of particularly tough materials (often to this property, and
silicone-based monomers are often used for this purpose. Table 2 contains
silicone-based materials). Hydrophobic comonomers add oxygen permeability to materials that the properties of common
CL materials
require and related
improvement copolymers,
to this property,including oxygen permeability,
and silicone-based monomerswater content,
are often usedmoduli,
for this and wear
purpose.
Table 2 contains the properties of common CL materials and related copolymers, including oxygen
permeability, water content, moduli, and wear time. Wear time is from the perspective of the
Materials 2019, 12, 261 6 of 35

time. Wear time is from the perspective of the maximum wear time of a CL before eye health issues
arise. More exhaustive resources comparing these properties are given elsewhere [3,4]. The effect
of copolymerization is particularly noticeable for rigid materials derived from PMMA with a large
reduction in the modulus, whereas the hydrogel classes of lenses have a much wider stable range of
moduli, but large variations in water content and oxygen permeability.

Table 2. Generalized properties of some common CL materials.

Oxygen Permeability
Material Water Content (wt %) Modulus (MPa) Wear Time (days) *
(Dk/t)
PMMA 0 0 1000 <1
PMMA-silicone 15 0
Silicone-HEMA (rigid) 10–100 0 10
HEMA hydrogel 10–50 30–80 0.2–2 1–7
HEMA-NVP
HEMA-MMA
Silicone (PDMS)
60–200 20–55 0.2–2 ~7–28
hydrogel
TRIS-DMA
PDMS-HEMA
PVA 10–30 60–70 <1
* Maximum wear time without extensive complications to the eye before lens disposal.

Full-density polymers utilize molecular weight and intermolecular forces to provide the strength
of the material; this is partly why PMMA has a high modulus. Other factors, such as the lens thickness
of the final lens, is important too, whereas the properties of very low-density polymers (10% of full
density, 90% air), such as porous materials are sensitive to small changes in cross-linking [46,47].
Another study demonstrated a reduction the Youngs modulus of up to 40% in a 90% porous material
due to inefficient cross-linking [48]. This could be relevant to very high-water-content hydrogels
on hydration from the final material properties and manufacturing considerations [49]. In fact,
Maldonado-Codina and Efron highlighted the need for improving processes between polymerization
batches and manufacturing methods. Other factors that are important include homogeneity of the
wall vertices, uniform pore size, etc.; all of which are not guaranteed to be consistent with FRP.
Moreover, if we consider SCLs to be porous cellular solids, these factors must be considered in future
designs [50]. Although FRP has been the workhorse for fabricating excellent CL materials, they may
not be producing entirely efficient networks for functional materials [51]. This could be another reason
why there are no drug-delivery CLs on the market today, in addition to the many reasons stated
by Dixon et al. [52]. Alternative polymerization mechanisms could be of interest to improve the
physical properties of CL materials. Other kinds of methods include catalysts or controlled radical
polymerization. One controlled method for radical polymerization is chain-transfer polymerization.
This has been a popular area of growth in polymer science, including examining the potential in other
bio-applications [53–55]. The chain-transfer agent accurately mediates the growth of the polymer chain,
so that the molecular weight can be pre-designed [39,56,57]. This results in a low-dispersity polymer,
meaning the resulting properties and structure are more reliable than FRP (Figure 4). There are
many examples of hydrogels produced using chain-transfer agents [58–60]. One specific example of
reverse addition fragmentation chain transfer (RAFT) polymerization encompasses silicone-based
polymers [61]. Other researchers also used RAFT to modify polyacrylic acid pH-responsive hydrogels
for drug delivery [60]. This opens the potential of RAFT-synthesized silicone- and conventional
hydrogels as CLs. Recently, Zhang et al. synthesized a promising RAFT-polymerized soft contact lens
based on polyallyl methacrylate and PEG components [62]. The lenses had low contact angles (<80◦ ),
high Dk values (>100 barrers), and elastic moduli ranging from 0.5–1.5 MPa, which are in the range of
the CL parameters given in Table 1.
Materials 2019, 12, x FOR PEER REVIEW 7 of 36

values (>100
Materials barrers),
2019, 12, and elastic moduli ranging from 0.5–1.5 MPa, which are in the range of the
261 7 ofCL
35
parameters given in Table 1.

Figure 4. 4. Schematic
Schematic for thefor the macromolecular
macromolecular structurebetween
structure differences differences
FRP and between FRP and
RAFT-polymerized
RAFT-polymerized
materials. The RAFTmaterials.
polymer can ThebeRAFT polymer
used to create acan
morebeordered
used tostructure
create a compared
more ordered structure
to FRP, which
compared
could to FRP, which
be important to the could be important
macromolecular to the macromolecular
structure structure
and final application of theand final application
material. Republished of
the material.
with Republished
the permission of Thewith the Society
Royal permission of The Royal
of Chemistry, Society
from of Chemistry,
Pushing from Pushing
the mechanical strengththe
of
PolyHIPEs
mechanicalup to the theoretical
strength of PolyHIPEs limitup
through
to the living radical
theoretical polymerization,
limit through livingY. Luo, A-N.
radical Wang, X. Gao,
polymerization,
8, 2012; permission conveyed through Copyright Clearance Center, Inc. [51].
Y. Luo, A-N. Wang, X. Gao, 8, 2012; permission conveyed through Copyright Clearance Center, Inc.
[51].
2.3. PMMA and Rigid Contact Lenses
2.3. PMMA and Rigid Contact Lenses
2.3.1. PMMA
2.3.1.Today,
PMMA PMMA CLs occupy a market share of about 1% [15]; however, they are a useful place to
begin to appreciate CLs materials—the properties of polymers that are suitable for ocular wear. One of
Today, PMMA CLs occupy a market share of about 1% [15]; however, they are a useful place to
the biggest issues with PMMA is that it has little to no oxygen permeability. This is due to the lack
begin to appreciate CLs materials—the properties of polymers that are suitable for ocular wear. One
of mobility of polymer chains preventing the flow of oxygen or internal water to mediate the flow
of the biggest issues with PMMA is that it has little to no oxygen permeability. This is due to the lack
of O2 (Figure 5). This occurs in PMMA due to intermolecular forces, such as dipole–dipole bonding
of mobility of polymer chains preventing the flow of oxygen or internal water to mediate the flow of
and physical entanglement that is prevalent between polymer chains. The dipoles are created by the
O2 (Figure 5). This occurs in PMMA due to intermolecular forces, such as dipole–dipole bonding and
negatively charged (electrochemical negative) oxygen compared with the adjacent positively charged
physical entanglement that is prevalent between polymer chains. The dipoles are created by the
(electrochemical positive) carbon and hydrogen atoms. Therefore, neighboring polymer chains can
negatively charged (electrochemical negative) oxygen compared with the adjacent positively
attract each other to provide thermodynamic stability to the polymer. These intermolecular forces
charged (electrochemical positive) carbon and hydrogen atoms. Therefore, neighboring polymer
also mean that PMMA has low free volume (space between polymer chains), meaning the chains do
chains can attract each other to provide thermodynamic stability to the polymer. These
not rotate or move easily. In addition, PMMA does not contain large pendant chains that prevent the
intermolecular forces also mean that PMMA has low free volume (space between polymer chains),
interaction of neighboring chains. All these factors together prevent the flow of oxygen through the
meaning the chains do not rotate or move easily. In addition, PMMA does not contain large pendant
polymer. However, functionalization of the PMMA surface can improve the hydrophilicity [63], which
chains that prevent the interaction of neighboring chains. All these factors together prevent the flow
would be useful to these CLs.
of oxygen through the polymer. However, functionalization of the PMMA surface can improve the
hydrophilicity [63], which would be useful to these CLs.
Materials 2019, 12, 261 8 of 35
Materials 2019, 12, x FOR PEER REVIEW 8 of 36

Figure 5.5.Schematic
Schematicforfor gas-permeability
gas-permeability mechanisms
mechanisms of CLofmaterials
CL materials from
from the the perspective
perspective of
of polymer
polymer chains. These 2D models represent how oxygen passes (or not) through
chains. These 2D models represent how oxygen passes (or not) through the molecular structurethe molecular
structure
of the CLofmaterial.
the CL material. These schematics
These schematics do notdo not show
show factorsfactors
such such as extensive
as extensive cross-linking
cross-linking or
or the
the macromolecular
macromolecular structure
structure thatthat would
would be present
be present in a in
3Dastructure.
3D structure.

In the
therecent
recent literature, PMMA
literature, PMMA has typically been utilized
has typically been as a reference
utilized as amaterial
reference for investigating
material for
various effects of CLs on the eye [64–67]. These works are some
investigating various effects of CLs on the eye [64–67]. These works are some of many with of many with a particular focusa
on the effect
particular of the
focus on PMMA
the effectlensofontheeyePMMAconditions,
lens such
on eye as astigmatism
conditions, such [64], as
strabismus
astigmatism [68], [64],
and
blepharoptosis
strabismus [68],[65]. andAlió et al. fitted patients
blepharoptosis [65]. Aliόwhoet had received
al. fitted post-corneal
patients who had refractive
received surgery with a
post-corneal
variety
refractive surgery with a variety of lens types, with RGP lenses showing the best results [64].etAn
of lens types, with RGP lenses showing the best results [64]. An interesting work by Li al.
showed
interestingfabrication
work by Li of et
a possible
al. showed new PMMA hybrid
fabrication lens with
of a possible newzincPMMA oxide quantum
hybrid dotszinc
lens with to reduce
oxide
UV exposure
quantum dots[69]. Very low
to reduce UVloadings
exposureof[69]. ZnOVery
quantum dots (0.017
low loadings wt %)quantum
of ZnO reduced dots
the transmittance
(0.017 wt %)
of UV light
reduced the by 50%, yet retained
transmittance suitable
of UV light optical
by 50%, yettransparency
retained suitableexpected
opticaloftransparency
a contact lensexpected
(Figure 6).of
Perhaps
a contactthe most
lens novel6).
(Figure advancement
Perhaps thefor mostPMMA
novellenses was the possibility
advancement for PMMA of lenses
developing
was thenanophotonic
possibility
lenses [70,71]. Acid-
of developing and hydroxyl-functionalized
nanophotonic lenses [70,71]. Acid- and fullerenes (C60 ) were attached
hydroxyl-functionalized to PMMA
fullerenes (Cto
60) try to
were
harness
attachedthe to photo-
PMMAand electro-activity
to try to harness the of photo-
the fullerene. However, these
and electro-activity ofnanophotonic
the fullerene. lenses havethese
However, now
been a focus oflenses
nanophotonic SCL materials
have nowinstead
been a[72].
focus of SCL materials instead [72].
However, all may not be bad for PMMA, as van der Worp discussed the relevance of PMMA as
scleral lenses [73]. In addition,
addition, PEG PEG grafted
grafted onto
onto PMMA
PMMA is is seen
seen asas aa prosthetic
prosthetic eye
eye replacement
replacement [74].[74].
Overall, these are only a few works amongst an enormous enormous amountamount of of literature
literature onon contact
contact lenses.
lenses.
The fact
fact remains
remainsthat thatPMMA
PMMAisisa very a very well-studied
well-studied polymer;
polymer; as such,
as such, the interest
the interest in developing
in developing new
new materials
materials derivedderived
fromfromPMMA PMMA is notis not exciting
exciting at at present.
present. Simply,the
Simply, thelack
lackofof many
many publications
involving PMMA in the modern literature is strong evidence that PMMA is not relevant in today’s
climate for forCLs.
CLs. TheTheonlyonly
hope hope
is thatisPMMA that can
PMMA continue
can tocontinue
be used for to fundamental
be used forunderstanding,
fundamental
along with the factors
understanding, along with thatthe
affect the eye
factors that gained
affect thewhen
eye using
gainedPMMA as a reference
when using PMMA asCL material.
a reference
For this reason, PMMA will remain a marginalized contact lens
CL material. For this reason, PMMA will remain a marginalized contact lens material for both material for both research and
commercial
research andpurposes.
commercial purposes.
Materials 2019, 12, 261 9 of 35
Materials 2019, 12, x FOR PEER REVIEW 9 of 36

Figure 6. PMMA
Figure 6. PMMA buttons
buttons loaded
loaded with
with ZnO
ZnO quantum
quantum dots.
dots. The
The fabricated
fabricated buttons
buttons would
would be
be suitable
suitable
for lathe-cutting manufacturing
for lathe-cutting manufacturing to form
form a final CL. Reprinted (and adapted) with permission from
a final CL. Reprinted (and adapted) with permission from
John-Wiley
John-WileyandandSons
Sons[69].
[69].

2.3.2. Other Rigid CLs

2.3.2. Other Rigid CLs
Modern rigid gas-permeable (RGP) lenses have moved away from PMMA, or significantly
Modern rigid gas-permeable (RGP) lenses have moved away from PMMA, or significantly
reduced the molar fraction of PMMA in many copolymers. Efron wrote an obituary for RGP lenses
reduced the molar fraction of PMMA in many copolymers. Efron wrote an obituary for RGP lenses
stating the reasons why these lenses are obsolete [75]. Nevertheless, RGP lenses (including PMMA)
stating the reasons why these lenses are obsolete [75]. Nevertheless, RGP lenses (including PMMA)
still account for about 14% of all lenses fit in the US as of 2017 [15]. Modern research concerning
still account for about 14% of all lenses fit in the US as of 2017 [15]. Modern research concerning RGP
RGP lenses is in regard to their application, treatment, and effect on eye conditions, rather than
lenses is in regard to their application, treatment, and effect on eye conditions, rather than
innovations on the material [76–78]. Eggnik et al. reported that a large-diameter RGP lens of unknown
innovations on the material [76–78]. Eggnik et al. reported that a large-diameter RGP lens of
composition was used to improve post-surgery treatment for laser in situ keratomileusis (LASIK)
unknown composition was used to improve post-surgery treatment for laser in situ keratomileusis
patients [79]. The success of RGP lenses lies in their rigidity, causing a reshaping of the cornea, which
(LASIK) patients [79]. The success of RGP lenses lies in their rigidity, causing a reshaping of the
was useful for some post-surgery treatment [80]. Soft lenses are sometimes unsuitable for treatment
cornea, which was useful for some post-surgery treatment [80]. Soft lenses are sometimes unsuitable
as they are very malleable, and therefore will shape to the user’s eye. These other works often use
for treatment as they are very malleable, and therefore will shape to the user’s eye. These other
commercially manufactured lenses to carry out their research; therefore, it is more difficult to know
works often use commercially manufactured lenses to carry out their research; therefore, it is more
the exact composition and methods by which these materials were synthesized. However, it is known
difficult to know the exact composition and methods by which these materials were synthesized.
that the typical composition of these lenses are based on fluoro silicone or siloxane (such as PDMS
However, it is known that the typical composition of these lenses are based on fluoro silicone or
and TRIS) acrylate moieties, alongside hydrophilic monomers such as HEMA, NVP, and methacrylic
siloxane (such as PDMS and TRIS) acrylate moieties, alongside hydrophilic monomers such as
acid (MAA) [4,76]. Baucsh & Lomb were assigned a patent for polysiloxane, copolymerized with
HEMA, NVP, and methacrylic acid (MAA) [4,76]. Baucsh & Lomb were assigned a patent for
urea moieties prepolymers to from RGP lenses [81]. The urea (or carbamides (CO(NH2 )2 ) moieties
polysiloxane, copolymerized with urea moieties prepolymers to from RGP lenses [81]. The urea (or
added hydrophilic properties. These vinyl end-capped prepolymers were then copolymerized with
carbamides (CO(NH2)2) moieties added hydrophilic properties. These vinyl end-capped
well-known monomers such as NVP, MAA, MMA, and TRIS to form the RGP lens.
prepolymers were then copolymerized with well-known monomers such as NVP, MAA, MMA, and
Although Efron’s prediction may not have come to pass, what is true is that there is a lack
TRIS to form the RGP lens.
of material innovation for RGP lenses. This simply could be due to the fact that RGP lenses are
Although Efron’s prediction may not have come to pass, what is true is that there is a lack of
unfashionable from a research perspective, particularly with the booming field of hydrogels. In fact,
material innovation for RGP lenses. This simply could be due to the fact that RGP lenses are
Efron first alludes to this by commenting on the marketing for SCLs over RGP lenses, and that the
unfashionable from a research perspective, particularly with the booming field of hydrogels. In fact,
lack of finance directed at improving these materials has caused their decline. Smart or wearable
Efron first alludes to this by commenting on the marketing for SCLs over RGP lenses, and that the
biosensors show promise for RGP lens materials [82], but even this field is being dominated by SCL
lack of finance directed at improving these materials has caused their decline. Smart or wearable
materials [83]. Perhaps the route to reinvigorating RGP lenses is through the growth of augmented
biosensors show promise for RGP lens materials [82], but even this field is being dominated by SCL
reality (AR) technology. Patents for the design of an AR contact lens have been assigned to companies
materials [83]. Perhaps the route to reinvigorating RGP lenses is through the growth of augmented
such as Samsung and RaayonNova in 2016 and 2017, respectively [84,85]. However, it is likely that the
reality (AR) technology. Patents for the design of an AR contact lens have been assigned to
companies such as Samsung and RaayonNova in 2016 and 2017, respectively [84,85]. However, it is
likely that the first lenses will borrow heavily from existing RGP lens materials. This is in contrast to
other smart CLs, which are often based on SCL materials [86].
Materials 2019, 12, 261 10 of 35

first lenses
Materials will
2019, 12,borrow heavily
x FOR PEER REVIEWfrom existing RGP lens materials. This is in contrast to other smart10CLs, of 36
which are often based on SCL materials [86].
2.4. HEMA-Derived Hydrogels
2.4. HEMA-Derived Hydrogels
HEMA and related hydrogels are a high-water content, oxygen-permeable polymeric material.
TheseHEMA and related
hydrogels hydrogels
can have are a high-water
water content between content,
20–80% oxygen-permeable polymeric material.
depending on the comonomers, with a
These hydrogels can have water content between 20–80% depending
hydrogel composed of only HEMA containing about 38% water. HEMA’s highly polar properties on the comonomers, with a
hydrogel
mean these composed
CLs have of only HEMAsuitable
generally containing about
wetting 38% water.
properties, HEMA’s
meaning highly
they are polar properties
comfortable. The
mean
oxygenthese CLs have generally
permeability of these suitable
gels iswetting
suitable properties, meaning
for longer wear,they
butarenotcomfortable.
to the same Theextent
oxygenof
permeability
silicone-based of lenses.
these gels is suitable forhydrogels
HEMA-derived longer wear, formbutan not to the same
important part of extent of silicone-based
the market, occupying
lenses.
about HEMA-derived
22% [15]. HEMAhydrogels is commonly formcopolymerized
an important part withofmonomers
the market,suchoccupying
as EGDMA, aboutMAA,
22% [15].
and
HEMA is commonly copolymerized with monomers such as EGDMA,
NVP. NVP and MAA increase the water content of hydrogels due the strong hydrophilic character MAA, and NVP. NVP and
MAA increase
arising from the watercarboxylic
amine, content of hydrogels due thegroups,
acid, hydroxyl strong hydrophilic
etc. Therefore,character
thesearising from amine,
comonomers also
carboxylic
influenceacid, hydroxyl groups,
the wettability etc. Therefore,
of the surface [87,88].these comonomers
The mechanical also influence
properties can be theimproved
wettability byofusing
the
surface [87,88]. The
a cross-linking mechanical
molecule, suchproperties can beglycol
as ethylene improved by using a cross-linking
dimethacrylate (EGDMA). EGDMA molecule, has
suchtwoas
ethylene
functionalglycol dimethacrylate
groups allowing the(EGDMA).
formationEGDMAof covalenthasbonds
two functional
between twogroups allowingpolymer
individual the formation
chains.
ofThis
covalent bonds
increases thebetween
mass of thetwopolymer
individual polymer chains.
dramatically, This increases
and improves the to
its ability mass
formofathe
gelpolymer
network.
dramatically,
However, the and improves
crosslinks itsreduce
also ability the
to form a gel network.
polymer-chain However,
motion, which the
cancrosslinks
be a factoralso reduce the
in swelling and
polymer-chain
oxygen transport motion, which
[88]. Thecan be a factor
water content in swelling and oxygenaffect
and cross-linking transport
the [88]. The water
modulus and content
oxygen
and cross-linking
permeability of affect the modulus
the hydrogels and oxygen
(Figure 7). As permeability
such, a balance of themust
hydrogels (Figure between
be reached 7). As such, a
these
balance mustwhen
parameters be reached between
designing a CLthese
for a parameters when designing a CL for a particular application.
particular application.

Figure 7. Schematic on the effect of cross-linking on the modulus, water-content percentage, and
Figure 7. Schematic on the effect of cross-linking on the modulus, water-content percentage, and
oxygen permeability. The increased cross-linking prevents (green) the polymer chains from swelling,
oxygen permeability. The increased cross-linking prevents (green) the polymer chains from swelling,
compared with lower-modulus gels.
compared with lower-modulus gels.

To improve CL materials, it is vital to better understand the properties of these hydrogels.

To improve CL materials, it is vital to better understand the properties of these hydrogels. The
The properties of HEMA-based hydrogels were shown to vary as a function of use by patients [89].
properties of HEMA-based hydrogels were shown to vary as a function of use by patients [89].
Tranoudis et al. measured the properties of lenses, such as total diameter, oxygen permeability,
Tranoudis et al. measured the properties of lenses, such as total diameter, oxygen permeability, and
and the back optic zone radius, at temperatures ranging from 20–35◦ and before/after 6 h of wear.
the back optic zone radius, at temperatures ranging from 20–35° and before/after 6 h of wear. All the
All the materials were altered with statistical significance; however, according to the summary tables,
materials were altered with statistical significance; however, according to the summary tables,
HEMA-VP 70% (meaning 70% water content) was moderately stable. In another study, the authors
HEMA-VP 70% (meaning 70% water content) was moderately stable. In another study, the authors
showed that free-to-bound water content was an important factor for the rate of dehydration and
showed that free-to-bound water content was an important factor for the rate of dehydration and
oxygen transport in SCLs [90]. The bound water to the polymer may be a factor in stability of
hydrogels, such as HEMA-VP 70%, compared with other gels. Tranoudis et al. published another
paper to more accurately characterize the tensile properties of the same organic hydrogels [91]. They
Materials 2019, 12, 261 11 of 35

oxygen transport in SCLs [90]. The bound water to the polymer may be a factor in stability of hydrogels,
such as HEMA-VP 70%, compared with other gels. Tranoudis et al. published another paper to more
accurately characterize the tensile properties of the same organic hydrogels [91]. They concluded
that hydrogels with high water content did not necessarily correlate with poor mechanical properties.
This is largely true, and is an uncomplicated way of summarizing the data. However, comparing
different polymer systems can be difficult due to the different intermolecular forces that exist to
provide stability (or lack of) based on different chemical compositions. There are properties of the
polymer structure which could reveal more factors that affect the mechanical properties of hydrogels.
Explanations by Ashby may reveal the reasons for inconsistent properties between batches of the same
polymeric material [50]. Porous cellular solids with varying wall thicknesses and lengths between
vertices are some of the factors that influence the mechanical properties of porous materials. Therefore,
it is important to study the polymer’s physical structure and polymerization mechanisms. Use of
1 H Nuclear Magnetic Resonance (NMR) relaxation times by Woźniak-Braszak et al. was a novel

characterization method used to probe the dynamics of free water in contact lenses [92], where they
showed an increase in free water in four-week-old lenses compared with new lenses (83% to 71%,
respectively). These studies together provide a more detailed understanding of hydrogels, which in
turn can be used for the better design of CLs.
Currently, modification of the HEMA-hydrogel structure is paving the way for new lenses,
innovations, and applications. Protein deposition on the eye remains a concern, particularly for SCL
materials based on HEMA [93,94]. Common comonomers, such as MAA and NVP, increase the protein
deposition. Both comonomers introduce hydrophilicity and electrochemical charge to the hydrogel,
which attracts the proteins from the tear film [93]. Lord et al. also showed that the protein uptake
could affect the water content of a HEMA-MAA hydrogel. This could be related to observations
by Tranoudis et al. where a HEMA-MAA hydrogel lost 15% water content across a 6 h period [89].
An interesting report by Borazjani et al. regarding the bacteria adhesion of Pseudomonas aeruginosa, a
risk factor in keratitis, to a HEMA-hydrogel was no less than that of a silicone hydrogel [95]. Borazjani
et al. also reported that adhesion of the bacteria was more related to the strain of bacteria than the lens
material. Another study by Szczotka-Flynn et al. demonstrated that biofilms of bacteria (particularly
Pseudomonas aeruginosa) were resistant to the antimicrobial action of CL solutions [96]. Dutta et al.
looked into the literature of this area by considering the material type, length of wear, and bacterial
strains on the cumulation of the bacteria on contact lenses [97]. New strategies to prevent this have
been in development since the early 2000s, including further modification of the lens material. A more
detailed and extensive article on antimicrobial strategies was published by Xiao et al. [98].
Grafting additional substances to HEMA has proven to be an effective method of modification
for improved lens functionality [99–101]. Some specific examples include grafts to reduce the protein
deposition or increase the anti-microbial action of contact lenses. A successful product based on
a HEMA hydrogel lens incorporated with silver nanoparticles (AgNPs) has been on the market
in the UK (MicroBlock® ). Other researchers looked at the impact of the monomer composition
of the HEMA hydrogel contact lens on AgNP uptake and performance [102]. They noticed that
HEMA-MAA-EGDMA gels had the strongest affinity to the nanoparticles, soaking in AgNPs from
10 to 20 ppm. Other interesting antimicrobial graft materials include melimine and polymyxin B.
Melimine is a synthesized antimicrobial peptide consisting of 29 amino acid units, and was covalently
bonded to HEMA-MAA-EGDMA using an acidic (pH = 5) buffer to induce the reaction to the pendant
acid groups on the lens [103]. This post-hydrogel modification may not be entirely practical for
manufacturing, but is interesting due to the excellent properties of the resulting hydrogels. Polymyxin
B is another anti-microbial macromolecule, and was grafted using an azobisisobutyronitrile (AIBN)
free-radical initiator during hydrogel synthesis [104]. The action of polymyxin B induces greater water
permeability of bacterial cells, eventually leading to bursting through the increased water uptake.
Sato et al. modified HEMA by copolymerization with moieties such as 2-methacryloxy ethyl phosphate
(MOEP) to facilitate drug delivery [105]. The MOEP adds additional anionic character, which was used
Materials 2019, 12, 261 12 of 35

to bind a model drug to the hydrogel. The drug release profile was a superior HEMA-MAA hydrogel
Materials 2019, 12, x FOR PEER REVIEW 12 of 36
due the stronger ionic group based on the chemical changes with pH.
Other modification
Other modification materials include the
materials include the incorporation
incorporation or or grafting
grafting of of surfactants.
surfactants. A A surfactant
surfactant
consists of a hydrophobic and hydrophilic component, and is primarily
consists of a hydrophobic and hydrophilic component, and is primarily used to promote used to promote the reduction
the
in surface tension between two immiscible liquids. Bengani et al. employed
reduction in surface tension between two immiscible liquids. Bengani et al. employed the novel use the novel use of
polymerizable
of polymerizable surfactants
surfactants attached
attachedtotoHEMAHEMAhydrogels
hydrogelstotoenhance
enhance wettability
wettability andand lubricating
lubricating
properties [106]. They achieved a 10 ◦ reduction in water-contact angle with about 2.4 wt % surfactant,
properties [106]. They achieved a 10° reduction in water-contact angle with about 2.4 wt %
which was which
surfactant, covalently bonded to bonded
was covalently the hydrogel
to the by UV polymerization.
hydrogel The low-surfactant
by UV polymerization. loading
The low-surfactant
meant that the HEMA-hydrogels remained below 45% water content,
loading meant that the HEMA-hydrogels remained below 45% water content, which indicates which indicates the power
the
power of such a technique. In this case, the hydrophilic component interacts with the aqueous film
of such a technique. In this case, the hydrophilic component interacts with the aqueous tear tear
and and
film the hydrophobic
the hydrophobic partpart
remains
remainsin the hydrogel
in the hydrogel(Figure
(Figure8).8).There
Thereisismuch
much modern
modern literature
literature
that still reports high rates of contact lens discontinuation due to discomfort and
that still reports high rates of contact lens discontinuation due to discomfort and dryness [107–109]. dryness [107–109].
This emphasizes the
This emphasizes the importance
importanceof ofnew
newtechniques,
techniques,suchsuchasassurfactant
surfactant loading/grafting
loading/grafting employed
employed by
by Bengani
Bengani et Other
et al. al. Otherusesuses of surfactants
of surfactants include
include useuse
as aasdrug
a drug delivery
delivery system
system forfor cyclosporine
cyclosporine A inA
in modified HEMA-hydrogels [110]. In this case, the surfactant leached out
modified HEMA-hydrogels [110]. In this case, the surfactant leached out of the hydrogel with the of the hydrogel with the
drug encapsulated
drug encapsulated within within surfactant
surfactant aggregates
aggregates (Figure
(Figure 9). This is
9). This is now
now becoming
becoming aa more
more researched
researched
topic, using a larger number of surfactants to deliver drugs [111–114].
topic, using a larger number of surfactants to deliver drugs [111–114]. These works have used These works have used aa
diverse range of surfactants, from cationic to non-ionic, with molecular weights
diverse range of surfactants, from cationic to non-ionic, with molecular weights ranging from about ranging from about
400–12,500 g − 1
400–12,500 g mol
mol−1. .This
Thiswide
widevariation
variationin in surfactant
surfactant properties
properties is is interesting,
interesting, suggesting
suggesting that
that the
the
hydrogel structure is highly adaptable to such
hydrogel structure is highly adaptable to such modifications.modifications.

Figure 8. Schematic
Figure 8. Schematic for
for the
the interaction
interaction between
between the
the aqueous
aqueous tear
tear film
film and
and aa surfactant
surfactant bonded
bonded with
with aa
hydrogel lens. Reprinted from Journal of Colloid and Interface Science, 445, Bengani, L.C.; Scheiffele,
hydrogel lens. Reprinted from Journal of Colloid and Interface Science, 445, Bengani, L.C.; Scheiffele,
G.W.; Chauhan,A.;
G.W.; Chauhan, A.;Incorporation
Incorporationofofpolymerizable
polymerizable surfactants
surfactants in in hydroxyethyl
hydroxyethyl methacrylate
methacrylate lenses
lenses for
for improving
improving wettability
wettability andand lubricity,
lubricity, 60, Copyright
60, Copyright 2014,
2014, withwith permission
permission fromfrom Elsevier
Elsevier [106].
[106].

In summary, HEMA-hydrogel CLs are in an exciting place. The ability to design new materials is
due to the flexible hydrogel structure composed from many functional groups. Essentially, the core of
the hydrogel has remained relatively unchanged, due to the principal properties that matter to CLs,
such as oxygen permeability, water content, wettability, etc. Modern HEMA hydrogel lenses have
evolved through modification of the hydrogel structure through techniques such as encapsulation
and grafting. Some of the materials used for modification were surfactants, nanoparticles, and
anti-microbial agents, all of which are diverse in themselves. As such, the works presented here are
only the beginning of an emerging field. There were also efforts to better understand the mechanical
properties of the HEMA-hydrogels, such as dehydration rates, bound and free water content, and
factors influencing protein absorption into the hydrogels. From a better understanding of hydrogel
Materials 2019, 12, 261 13 of 35

properties, new manufacturing processes can evolve to further improve the material specifications.
This is encouraging progress for designing better materials, which will only keep evolving as more
and more
Materials chemical
2019, 12, x FORmodification
PEER REVIEW techniques and materials are employed. 13 of 36

Figure 9.9.Drug-loaded
Figure Drug-loaded hydrogel
hydrogel loaded
loaded withwith surfactants.
surfactants. The aggregation
The aggregation and of
and leaching leaching of the
the surfactant
surfactant
acts actsdelivery
as a drug as a drug delivery
vehicle. vehicle.from
Reprinted Reprinted from Biomaterials,
Biomaterials, 30,Thomas,
30, Kapoor, Y.; Kapoor,J.C.;
Y.; Thomas, J.C.;
Tan, G.; John,
Tan, Chauhan,
V.T.; G.; John,A.V.T.; Chauhan, A.soft
Surfactant-laden Surfactant-laden
contact lenses forsoft contact delivery
extended lenses for extended delivery
of ophthalmic of
drugs, 867,
ophthalmic2008,
Copyright drugs, 867,
with Copyrightfrom
permission 2008,Elsevier
with permission
[110]. from Elsevier [110].

2.5. Silicone-Derived Hydrogels

In summary, HEMA-hydrogel CLs are in an exciting place. The ability to design new materials
is due to the flexible
Silicone-based hydrogel
hydrogels arestructure
the mostcomposed fromofmany
common type functional
CL material groups.
today, Essentially,
occupying the
about 64%
core of the hydrogel has remained relatively unchanged, due to the principal properties
of the US market [15]. This includes silicone, silioxanes, fluorosiloxanes, and derivative materials. that matter
to CLs,
Their such as oxygen
popularity permeability,
is linked water
to the fact that these content, wettability,
CLs have the highestetc.oxygen
Modern HEMA hydrogel
permeability lenses
of all contact
havematerials
lens evolved (>100
through modification
Dk, typically). of the
Silicone CLshydrogel
are often structure through techniques
durable, originating from the high such as
Si–O
encapsulation and grafting. Some of the materials used for modification
bonding energy, often with a higher modulus than conventional polymer hydrogels. This typically were surfactants,
nanoparticles,
applies to RGPand anti-microbial
lenses, as the modernagents, all of which
silicone are has
hydrogel diverse in themselves.
a similar modulus As such, the works
to HEMA-derived
presented here are only the beginning of an emerging field. There were
hydrogels. The high modulus is linked to causing irritation to the eye, such as the conjunctiva also efforts to better
of the inner eyelid [4]. In fact, the discomfort and dryness of silicone-based lenses are two bound
understand the mechanical properties of the HEMA-hydrogels, such as dehydration rates, of the
and free
main waterfor
reasons content, and factors influencing
users’ discontinuation protein absorption
[107,109,115,116]. intothe
Specifically, thewettability
hydrogels.ofFrom a better
the lens and
understanding of hydrogel properties, new manufacturing processes can evolve
the incompatibility with the cornea environment in vivo requires detailed study to improve these to further improve
the material[117].
parameters specifications.
The patentThis is encouraging
literature contains muchprogress
aboutforimproving
designingthe better materials,
wettability whichwith
of lenses, will
only keep such
companies evolving as more and
as CooperVision more
[118] and chemical modification
Johnson and Johnson [119]techniques and for
having filed materials
patentsare
to
employed.
develop such lenses. This includes using many combinations of comonomers with silicone monomers.
However, similarly to the preceding sections, modern silicone lenses have not deviated from the base
2.5. Silicone-Derived
materials since theyHydrogels
were first developed. Nowadays, new chemical techniques look to evolve the
silicone CL material hydrogels
Silicone-based beyond its are
predecessors.
the most common type of CL material today, occupying about
Silicone hydrogels have commonly
64% of the US market [15]. This includes been silicone,
subject tosilioxanes,
post-fabrication processes. and
fluorosiloxanes, Some, such as
derivative
plasma
materials.treatment, are used is
Their popularity to linked
improve lensfact
to the wettability
that these byCLs
manufacturers [120–122].
have the highest oxygen This technique
permeability
has
of all contact lens materials (>100 Dk, typically). Silicone CLs are often durable, originatingCLs
been proven very effective; however, there are still a number of issues relating to silicone from[123].
the
Santos et al.bonding
high Si–O suggested that protein
energy, absorption
often with a higherof modulus
commercial silicone
than hydrogelpolymer
conventional lenses was independent
hydrogels. This
of the plasma
typically treatment
applies to RGP[124]. They summarized
lenses, as the modern that the inherent
silicone hydrophobic
hydrogel has acharacter
similar of the lenses
modulus to
helped in reducing the deposition. With this in mind, new chemical modification
HEMA-derived hydrogels. The high modulus is linked to causing irritation to the eye, such as the techniques, with
conjunctiva of the inner eyelid [4]. In fact, the discomfort and dryness of silicone-based lenses are
two of the main reasons for users’ discontinuation [107,109,115,116]. Specifically, the wettability of
the lens and the incompatibility with the cornea environment in vivo requires detailed study to
improve these parameters [117]. The patent literature contains much about improving the
wettability of lenses, with companies such as CooperVision [118] and Johnson and Johnson [119]
 Silicone hydrogels have commonly been subject to post-fabrication processes. Some, such as
plasma treatment, are used to improve lens wettability by manufacturers [120–122]. This technique
has been proven very effective; however, there are still a number of issues relating to silicone CLs
[123]. Santos et al. suggested that protein absorption of commercial silicone hydrogel lenses was
independent of the plasma treatment [124]. They summarized that the inherent hydrophobic
Materials 2019, 12, 261 14 of 35
character of the lenses helped in reducing the deposition. With this in mind, new chemical
modification techniques, with or without plasma treatment, are becoming of interest. The use of
orhydrophilic
without plasma and hydrophobic
treatment, are lipids by Bhamla
becoming et al. The
of interest. investigated the wetting
use of hydrophilic andand dewetting
hydrophobic
character
lipids of a Balafilicon
by Bhamla A lens [125].
et al. investigated theThey showed
wetting that a hydrophobic
and dewetting character lipid (meibum) could
of a Balafilicon A lensreduce
[125].
They showed that a hydrophobic lipid (meibum) could reduce the wetting area on the lens surface byto
the wetting area on the lens surface by nearly 70% in 50 s. Lin et al. modified the lens surface
adhere70%
nearly polyelectrolyte
in 50 s. Lin et monolayers
al. modified the (PEMs) of chitosan
lens surface and polyelectrolyte
to adhere hyaluronic acid [126]. Chitosan
monolayers (PEMs)isofa
naturallyand
chitosan derived polymer
hyaluronic acid(from
[126].chitin)
Chitosanwithishigh bioavailability
a naturally derivedoriginating
polymer (from fromchitin)
the hydroxyl
with highand
amine groupsoriginating
bioavailability within the structure,
from the hydroxyl lending
and itself
aminetogroupslens within
modification. They lending
the structure, modified the
itself
toplasma-treated
lens modification. silicone
They surface to create
modified negatively charged
the plasma-treated groups,
silicone surfacewhich allowed
to create the formation
negatively chargedof
the positively
groups, charged the
which allowed chitosan layer.ofThen,
formation the negatively
the positively charged charged
chitosanhyaluronic
layer. Then,acid the
formed a layer
negatively
on this surface
charged hyaluronicto form
acidalternative
formed a layer layers.onThe
thiscontact
surfaceangle
to formwasalternative
reduced from 90°The
layers. in the mother
contact lens
angle
to up
was to 50° from
reduced in the90 ◦ in the motherlenses.
PEM-modified up to 50◦ ainmodified
lens toSimilarly, chitosan was
the PEM-modified alsoSimilarly,
lenses. used successfully
a modified by
Tian et al. to form a chitosan layer on the surface of the lens (Figure
chitosan was also used successfully by Tian et al. to form a chitosan layer on the surface of the lens 10) [127]. Hydroxypropyl
trimethyl
(Figure 10) ammonium chloride chitosan
[127]. Hydroxypropyl trimethylisammonium
a quaternary ammonium
chloride chitosansaltisand is positively
a quaternary charged,
ammonium
which
salt andfacilitates
is positively thecharged,
formation of self-assembled
which layers. These
facilitates the formation pendant chemical
of self-assembled layers.groups
Thesecould lead
pendant
to furthergroups
chemical modification
could leadof thetolens. Thissen
further et al. modified
modification of thesilicone lenses with
lens. Thissen a poly
et al. ethylene
modified oxide
silicone
(PEO)with
lenses graft to ethylene
a poly the surface oxide for
(PEO) anti-biofouling properties
graft to the surface [128]. First,properties
for anti-biofouling they used [128].plasma
First,
polymerization
they used plasmatopolymerization
adhere allyl amine to the surface
to adhere of the
allyl amine tolens, and then
the surface ofused a reducing
the lens, and then solution
used aof
sodium cyanoborohydrate
reducing solution of sodium and PEO to complete
cyanoborohydrate andthe
PEO PEO graft. A similar
to complete the PEO process
graft. A using acrylic
similar acid
process
was performed
using acrylic acid bywasDutta et al. to attach
performed by Dutta a melamine-derived
et al. to attach apeptide (Mel4) to thepeptide
melamine-derived surface (Mel4)
of a range
to
of silicone lenses (lotrafilcon A, lotrafilcon B, somofilcon A, senofilcon
the surface of a range of silicone lenses (lotrafilcon A, lotrafilcon B, somofilcon A, senofilcon A, andA, and comfilcon A) [129].
They alsoA)used
comfilcon [129].anThey
acid also
buffer
usedsolution
an acidtobuffer
covalently
solutionbond the Mel4 bond
to covalently peptide theto the peptide
Mel4 surface to ofthe
the
lenses [130]. The peptide improved the anti-microbial properties of the
surface of the lenses [130]. The peptide improved the anti-microbial properties of the lenses withoutlenses without causing other
irritations
causing to the
other tested subjects
irritations (rabbits).
to the tested subjects (rabbits).

Figure 10. Schematic for the adhesion of a self-assembled layer onto the surface of silicone hydrogel.
Figure 10. Schematic for the adhesion of a self-assembled layer onto the surface of silicone hydrogel.
Reprinted (and adapted) from Colloids and Surfaces A, 558, Tian, L.; Wang, X.; Qi, J.; Yao, Q.; Oderinde,
Reprinted (and adapted) from Colloids and Surfaces A, 558, Tian, L.; Wang, X.; Qi, J.; Yao, Q.;
O.; Yao, C.; Song, W.; Shu, W.; Chen, P.; Wang, Y. Improvement of the surface wettability of silicone
Oderinde, O.; Yao, C.; Song, W.; Shu, W.; Chen, P.; Wang, Y. Improvement of the surface wettability
hydrogel films by self-assembled hydroxypropyltrimethyl ammonium chloride chitosan mixed colloids,
of silicone hydrogel films by self-assembled hydroxypropyltrimethyl ammonium chloride chitosan
422, Copyright 2018, with permission from Elsevier [127].
mixed colloids, 422, Copyright 2018, with permission from Elsevier [127].
Other materials were of interest as new grafting or encapsulation components into silicone-based
hydrogels. Tuby et al. used Zn-CuO particles as an anti-microbial film on CLs composed of silicone
hydrogels (Bausch&Lomb) [131]. They used a base bath (pH = 8) loaded with the nanoparticles to soak
into the lenses to induce uptake of the nanoparticles by the hydrogel. They also commented that the
nanoparticles did not leech easily from the structure, which would be an important safety concern.
Jung et al. used a polymer nanoparticle (propoxylated glyceryl triacrylate) to deliver the drug timolol,
which is used for glaucoma treatment [132]. The lenses also incorporated the nanoparticles through
a soaking method, which was a phosphate buffer solution (pH ≈ 7.4). Although the nanoparticles
Materials 2019, 12, 261 15 of 35

did not affect optical transparency, they noted an undesirable decline in the water content, oxygen
permeability, and modulus. Willis et al. grafted hydrophilic phosphorylcholine (PC) to the surface
of silicone lenses using several Michael-type addition steps [133]. The coating reduced the water
contact angle by nearly 50◦ , which was an impressive result. One concern they had was the lowering
modulus by 0.5 MPa in the PC-treated lenses compared with unmodified lenses. Wang et al. used an
interpenetrating network of silicone and PC to synthesize the hydrogel to achieve similar wettability
results [134]. A 35–80 nm layer of PC was also grafted onto silicone using UV light (305 and 365 nm) to
induce the polymerization graft [135]. The surface graft did not affect the oxygen permeability and
modulus, but reduced the lysozyme and fibrinogen deposition and water contact angle. Wang et al.
grafted polyethylene glycol methacrylate (PEGMA) to silicone using UV light again, and again the
hydrogels retained excellent properties, such as >140 Dk and >1 MPa elastic modulus [136]. Synthesis
of silicone hydrogels also incorporating PEGMA by Lin et al. successfully reduced the lysozyme and
human serum albumin (HSA) deposition by 82% and 77%, respectively [45]. However, the increasing
volumes of PEGMA affected other properties of the lens, such as increasing brittleness above 20%
PEGMA content. The PEGMA polymer brush is a known anti-biofouling material [137,138]. Its low
cost and easy incorporation is likely worth pursing for other CLs. These studies highlight the impact of
surface modification techniques on improving CL properties. However, manufacturing aspects need
to be considered to realize these modifications in a new generation of CLs.
In summary, silicone hydrogel lenses are targets for highly biocompatible coatings that can be
grafted/encapsulated to the surface of, or within, the lenses by chemistry techniques. In these
experiments, the performance of the lens was improved, particularly towards anti-biofouling
applications. Hydrophilic anti-biofouling materials are being applied more often to silicone hydrogel
CLs [139]. This emphasizes the innovations which silicone-based hydrogel lens materials are
undergoing. For silicone hydrogel, there is a two-fold benefit of these anti-biofouling materials:
(1) These hydrophilic grafts/modifications are the route to anti-biofouling behavior, and; (2) they are
hydrophilic, increasing the wetting character of the lens. This effect is also relevant to HEMA-based
lenses; however, it is more impactful to silicone lenses, given their inherent wettability disadvantages
and market size. Continued improvements to these materials will result in continued market
dominance for silicone-based hydrogel CLs.

2.6. Other Contact Lens Materials

2.6.1. Polyvinyl Alcohol Hydrogels

PVA is a synthetic polymer that contains many hydroxy (–OH) groups, one in each repeating
monomer unit. This is the source of PVA’s excellent hydrophilic and biocompatible properties [140].
As such, it is clear why this material is an interesting contact lens material. PVA hydrogels were of
attention to several researchers in the early 1990s [17,18]. Even without modification, PVA CL hydrogels
were also shown to have lower protein absorption rates than HEMA and MMA/VP hydrogels [18].
However, it wasn’t until the late 1990s that this material broke into the market in the form of the
Nelfilcon A lens [16]. These lenses have a Dk of about 26 barrers and high wettability, which is
acceptable for daily wear. Produced by CIBA vision, the PVA hydrogel was synthesized using
water as the solvent and produced inside a transparent mold to allow UV initiation of the polymer
solution. Water was an environmentally friendly choice of solvent which also did not hinder the
polymerization stages. Buhler et al. formed the PVA hydrogel by adding a new functional group to
facilitate cross-linking between chains [16]. In acidic conditions and a suitably reactive dialdehyde
group, PVA can be functionalized with a stable cyclic-acetal group. This can then crosslink with other
PVA chains to form a crosslinked hydrogel. More recently, PVA has been used as a tool for producing
more comfortable lenses [141,142] or to facilitate the loading of a colored pigment into the lens [143].
One of the comfort mechanisms include elution of an unbound PVA polymer from the contact lens into
the tear film. Non-crosslinked PVA with an approximately 47,000 molecular weight was soaked into a
Materials 2019, 12, 261 16 of 35

cross-linked PVA lens. The high molecular weight and bioavailability meant that PVA leeched out
of the lens to lubricate the eye as a sort of artificial tear component [142,144]. Researchers identified
that the higher molecular weight species took longer to elute from the lens than lower molecular
weight species. Although these examples are strictly not using PVA hydrogels, they highlight the
importance of this material for other ophthalmic applications. This even extends to areas such as
corneal replacement [145].
There has been some investigation into the modification of PVA hydrogel CLs. Xu et al.
modified the PVA structure with β-cyclodextrins (β-CDs) to improve drug-loading of puerarin and
acetazolamide [146]. They functionalized both the β-CDs and PVA with a methacrylate moiety
with N,N-dimethyl-4-pyridinamine and glycidyl methacrylate to achieve the necessary functionality.
Then, both methacrylated species were copolymerized to form the hydrogel. This method also
resulted in incorporation of 30 wt % of β-cyclodextrin. Sun et al. also used a functionalized β-CD
polymer incorporated into a PVA film for the delivery of voriconazole [147]. A β-CD solution
containing dissolved voriconazole was mixed with a PVA solution and then used to form electrospun
nanofibers. PVA cross-linked with cellulose offers another a potential route to improved contact
lens materials [148,149]. Cellulose is a naturally occurring polymer with enormous potential for
bio-applications [150]. Mihranyan chemically bound the cellulose microcrystal “whiskers” onto
the surface of PVA using a 2,2,6,6-tetramethyl-1-piperidine oxoammonium salt (TEMPO)-mediated
surface oxidation [149]. The TEMPO technique is a special technique used for regioselective oxidation
of cellulose to preserve crystallinity [151]. The technique only functionalizes the surface of the
material. Although the physical properties of the PVA hydrogels improved, the opaque material
would not be ideal as a CL material. Tummala et al. incorporated nanocellulose, a transparent
version of cellulose, as nanofibrils or nanocrystals into a PVA hydrogel, improving the physical
properties [148]. In addition, the lens retained excellent optical properties, with >90% transparency to
visible light (Figure 11). They used a mixed solvent system of water:dimethyl sulfoxide (DMSO) at
ratios between 60–80% DMSO content to facilitate the solvation of the nanocellulose components. These
nanocellulose PVA hydrogels were investigated for their light-scattering properties by Tummala et al.
in another work [152]. The hydrogel composition and angle of light affected the scattering of
light in the range of 3% to 40%, with the nanocellulose-functionalized PVA hydrogel reducing the
scattering. The nanocellulose hydrogels were then used to encapsulate acrylic-acid-functionalized
chitosan nanoparticles as a vehicle for a lysozyme-triggered release of a model drug. Lysozyme
(0.2 mM)-mediated hydrolysis of the chitosan-functionalized nanoparticle would trigger the release of
the drug.
The PVA hydrogel is a relatively new class of hydrogel lens compared with silicone- and
HEMA-hydrogels. The low cost, high bioavailability, and wettability properties mean PVA hydrogels
will remain important to the CL industry. This means there is a lot of design space for investigation into
modifying the structure to improve lens functionality. There are an increasing number of modification
techniques and materials that have yet to be explored with PVA hydrogels. The secondary alcohol
groups within the polymer chain are very easily modified for grafting, as shown by cellulose or
β-cyclodextrin incorporation. As with HEMA- and silicone-hydrogels, the grafting or encapsulation
of anti-microbial agents is just one of many interesting avenues of research that is possible for
PVA hydrogels.
Materials 2019, 12, 261 17 of 35
Materials 2019, 12, x FOR PEER REVIEW 17 of 36

Figure 11. Optical image (left) and the transmittance data (right) for PVA hydrogels
hydrogels incorporating
incorporating
nanocellulose. Reprinted (adapted) with permission from Tummala, G.K.; Rojas,
nanocellulose. Reprinted (adapted) with permission from Tummala, G.K.; Rojas, R.; Mihranyan,
Mihranyan, A.;
A.;
with nanocellulose
Poly(vinyl alcohol) hydrogels reinforced with nanocellulose for
for ophthalmic
ophthalmic applications:
applications: general
characteristics and optical properties, Journal of Physical Chemistry B, 2016,
characteristics 2016, 120,
120, 13094.
13094. Copyright
2016 American Chemical Society [148].

2.6.2.The
Hyaluronic-Acid-Modified Hydrogels
PVA hydrogel is a relatively new class of hydrogel lens compared with silicone- and
HEMA-hydrogels.
Hyaluronic acidThe(HA)lowis a cost, high bioavailability,
hydroscopic biopolymer thatand wettability
naturally occurs properties mean body.
within the human PVA
hydrogels will remain important to the CL industry. This means there is a lot of design
HA has already been mentioned in previous sections. Here, we explain why this material is significantly space for
investigation
impacting CLinto modifying
research. Thisthe
is structure to improve
an important materiallens
forfunctionality.
a wide range There are an increasing
of tissue-engineering
number of modification techniques and materials that have yet to be explored
purposes [153]. From the chemical structure, we can see why it is useful for incorporating with PVA hydrogels.
into
The secondary alcohol groups within the polymer chain are very easily
CL materials (Figure 12). The amino acid and hydroxyl groups present in each repeating modified forunit
grafting,
provideas
shown
the by cellulose
necessary or β-cyclodextrin
hydrophilic incorporation.
character, leading As with HEMA-
to high biocompatibility. As and
such,silicone-hydrogels,
this material has beenthe
grafting or encapsulation of anti-microbial agents is just one of many interesting avenues
of interest in developing ophthalmic treatments, such as lubricating solution [154] or contact lens of research
that is possible
modification for PVA
[155]. Thehydrogels.
incorporation of HA was shown not to affect the surface morphology of
the CL even after 12 h of wear, showing the stability of these modifications [156]. HA is typically a
2.6.2. Hyaluronic-Acid-Modified
graft/encapsulating Hydrogels
material to other established CL hydrogels. The commercial success of HA is
apparent
Hyaluronic acid (HA) is a hydroscopicsolution
with the Bausch&Lomb Biotrue™ and Open30
biopolymer (by Safilens)
that naturally occurslenses incorporating
within the human
HA
body.asHA a lubricating
has already agent. Other ophthalmic
been mentioned treatments
in previous and
sections. modifications
Here, we explaininclude HA
why this use as is
material a
treatment
significantlyfor dry eyes, [157,158]
impacting modification
CL research. This ofis the
an lens materialmaterial
important [126,159,160],
for aand drug-delivery
wide range of
mechanism
Materials 2019, [161–163].
tissue-engineering
12, x FORpurposes [153]. From the chemical structure, we can see why it is useful
PEER REVIEW 18 offor
36
incorporating into CL materials (Figure 12). The amino acid and hydroxyl groups present in each
repeating unit provide the necessary hydrophilic character, leading to high biocompatibility. As
such, this material has been of interest in developing ophthalmic treatments, such as lubricating
solution [154] or contact lens modification [155]. The incorporation of HA was shown not to affect
the surface morphology of the CL even after 12 h of wear, showing the stability of these
modifications [156]. HA is typically a graft/encapsulating material to other established CL
hydrogels. The commercial success of HA is apparent with the Bausch&Lomb Biotrue™ solution
and Open30 (by Safilens) lenses incorporating HA as a lubricating agent. Other ophthalmic
treatments and modifications include HA use as a treatment for dry eyes, [157,158] modification of
the lens material [126,159,160], and drug-delivery mechanism [161–163].
Figure 12.Chemical
Figure 12. Chemicalstructure of hyaluronic
structure acid. The
of hyaluronic acid.repeating unit within
The repeating unitthewithin
polymer
theis polymer
hydrophilic
is
with many highly polar groups, such as the amine, acid, and hydroxy groups.
hydrophilic with many highly polar groups, such as the amine, acid, and hydroxy groups.

HA was investigated as a reusable wetting agent, and considered as a vehicle for the delivery
HA was investigated as a reusable wetting agent, and considered as a vehicle for the delivery of
of timolol within a silicone hydrogel lens [164]. HA is hydroscopic, meaning it was used to add
timolol within a silicone hydrogel lens [164]. HA is hydroscopic, meaning it was used to add water
water content to a material without a significant reduction in the other hydrogel components of DMA
content to a material without a significant reduction in the other hydrogel components of DMA and
and TRIS [160]. All of the silicone hydrogels Paterson et al. produced had a water contact angle
TRIS [160]. All of the silicone hydrogels Paterson et al. produced had a water contact angle of less
than 50°, emphasizing the wettability qualities of HA. The wetting agent was a copolymer of PEG
and HA, which was first copolymerized before being soaked into the HA-modified silicone
hydrogels. Van Beek et al. crosslinked/physically entrapped HA into HEMA hydrogels by using
1-ethyl-3-(3-dimethylaminopropyl)-carbondiimide (EDC)/diaminobutane-4 dendimer to provide the
 Materials 2019, 12, 261 18 of 35

of less than 50◦ , emphasizing the wettability qualities of HA. The wetting agent was a copolymer
of PEG and HA, which was first copolymerized before being soaked into the HA-modified silicone
hydrogels. Van Beek et al. crosslinked/physically entrapped HA into HEMA hydrogels by using
1-ethyl-3-(3-dimethylaminopropyl)-carbondiimide (EDC)/diaminobutane-4 dendimer to provide the
necessary functionality for a reaction [159]. Furthermore, HA in very low amounts (5 g/L solution)
reduced the water contact angle of the hydrogels by about 15–25◦ . These HA-modified hydrogels
also showed less lysozyme absorption, which can often be a criticism of HEMA-derived hydrogels.
However, large molecular weight (Mw ) HA (169 kDa) had reduced optical transparency between
500–800 nm versus the lower Mw HA (35 kDa). On the other hand, the 169 kDa HA was responsible for
the lowest amount of protein deposition. Korogiannaki et al. covalently bonded HA to the surface of
HEMA by using a nucleophilic Michael-addition thiol-ene “click” chemical reaction [165]. These lenses
retained an optical transparency level of >92%, and decreased the water contact angle and rate of
lens dehydration. A more detailed mechanism of the covalent bonding of HA to the HEMA hydrogel
structure was presented by Deng et al. [166] “Click” chemistry was used with adipic acid dihydrazde
(ADH) to anchor HA to HEMA. HEMA was first oxidized to provide the functionality for bonding the
ADH-HA anchor. The lens properties virtually remained unchanged, such as the modulus and optical
properties (Figure 13). They also measured a reduction in the rate of dehydration of the lens compared
with the unmodified lenses. Weeks et al. used UV light to covalently bond a methacrylate modified
HA to HEMA and silicone hydrogel lenses [167]. In all cases, the HA-modified hydrogels had a greatly
reduced water-contact angle and reduction of lysozyme absorption. They also pointed out that HA
with little or no methacrylation on the surface would not prevent the interaction of the protein with
the surface of the hydrogel, whereas if HA was entrapped inside the hydrogel, the protein could not
Materials
interact2019,
with12,the
x FOR PEER REVIEW
surface at as many points, preventing its deposition. 19 of 36

Figure
Figure13.
13.Optical
Opticalproperties
propertiesofofHA-HEMA,
HA-HEMA,oxidized-HEMA
oxidized-HEMA(OX-HEMA),
(OX-HEMA),and andunmodified
unmodifiedHEMA
HEMA
lenses.
lenses.The
The transparent hydrogels can
transparent hydrogels canbebeseen
seenjust
justabove
abovethethe ruler
ruler markings.
markings. Reprinted
Reprinted (adapted)
(adapted) with
with permission
permission from from
Deng,Deng, X.; Korogiannaki,
X.; Korogiannaki, M.; Rastegari,
M.; Rastegari, B.; J.;Zhang,
B.; Zhang, J.; Chen,
Chen, M.; Fu, Q.;M.; Fu, Q.;
Sheardown,
Sheardown, H.; Filipe,
H.; Filipe, C.D.M.; C.D.M.;
Hoare, Hoare,chemistry-tethered
T. “Click” T. “Click” chemistry-tethered hyaluroniccontact
hyaluronic acid-based acid-based contact
lens coatings
lens coatings improve lens wettability and lower protein adsorption, ACS Applied Materials
improve lens wettability and lower protein adsorption, ACS Applied Materials and Interfaces, 2016, and8,
Interfaces, 2016, 8, 22064.
22064. Copyright Copyright
2016 American 2016 American
Chemical Society Chemical
[166]. Society [166].

HAisis an
HA an increasingly
increasingly popular
popular material
materialfor for the
the modification
modification ofof both
both HEMA-hydrogel
HEMA-hydrogel and and
silicone-hydrogelCLs.
silicone-hydrogel CLs.TheThehigh
highbioavailability
bioavailabilityand andstraightforward
straightforwardincorporation
incorporationmethods
methodshavehave
alreadyseen
already seen recent
recent commercial
commercial success
successforforHA.
HA.InInthese
thesecases, HA
cases, HA was a lubricating
was agent
a lubricating rather
agent than
rather
any physical/chemical
than any physical/chemical modification of theoflens
modification thematerial. RecentRecent
lens material. works works
regarding HA are HA
regarding exciting,
are
demonstrating
exciting, the abilitythe
demonstrating that HA can
ability thatalter,
HAtune,
can or improve
alter, tune, the propertiesthe
or improve of contact lenses.
properties HA can
of contact
be entrapped
lenses. HA can or be chemical-bound to the hydrogel
entrapped or chemical-bound to provide
to the hydrogel increased wettability
to provide increasedor resistanceorto
wettability
protein deposition.
resistance to protein One of the most
deposition. One limiting factors
of the most for the
limiting widerfor
factors application
the widerof HA is the of
application high
HAcost.
is
the high cost. Although dilution can reduce the cost, the effectiveness of HA will diminish. Once this
issue has been overcome, HA will be commonly incorporated into new lenses.

3. Outlook for CL Materials

3.1. Drug Delivery

Materials 2019, 12, 261 19 of 35

Although dilution can reduce the cost, the effectiveness of HA will diminish. Once this issue has been
overcome, HA will be commonly incorporated into new lenses.

3. Outlook for CL Materials

3.1. Drug Delivery

Today, CLs are increasingly seen as a tool for specific ophthalmic treatments that require delivery
of a drug to the eye. The low bioavailability (about 5%) of common ophthalmic treatments, such as
eye drops, is a concern to delivering effective treatments [168]. In turn, practitioners rely on new
lenses to be developed to improve these treatments, which is reliant on material scientists developing
new materials. This is evident by the publication of review papers in the last few years [27,28,169].
These reviews contain significant detail on the latest drug delivery mechanisms, materials, and relevant
literature of modern drug delivery, including general drug delivery within the body. The majority of
the referenced literature is after the year 2000, indicating the significant advances and interest in the
field within the last 20 years. In this paper, we highlight the trends in the CL materials used for ocular
drug delivery. Some of the methods investigated include drug-loading by nanoparticle- or polymeric
encapsulation [170–173], β-cyclodextrin delivery [40,174–176], molecular imprinting [177–179], and
solution soaking [37,180–182]. Molecular imprinting involves fabrication of the hydrogel alongside the
drug. Typically, increasing crosslinking and addition of a porogenic solvent facilitates this by creating
more cavities for residing the drug [179]. The nanoparticles used in these examples, which were all
polymeric, encapsulated the drug. The biocompatible polymers responded to the ocular environment
to release the drug. Ethyl cellulose and lactic-co-glycolic acid are two examples [171,172] These are
all of scientific interest; however, more should be done to access their practical application. This can
include clinical trials or practicality of manufacturing.
The properties of an incorporated material into CLs can be used as improved drug-binding
mechanisms [183]. For example, incorporation of ionic monomers can create binding sites for a polar
drug to bind to (Figure 14), meaning the lens can retain the drug until it is placed onto the eye. MAA,
for example, is one comonomer commonly used for the formation of hydrogels, but which also has an
anionic group to facilitate drug-binding. Another clever use of new materials was the use of pendent-
or copolymerized cyclodextrins for introducing both hydrophilic and hydrophobic character to the
CL [174,176]. The inside of the 7-unit ring of cyclodextrin is hydrophobic, ideal for drug complexing,
whereas the outside of the molecule is hydrophilic to provide the lens with suitable biocompatibility
(Figure 15). Dos Santos et al. loaded hydrocortisone and acetazoamide into a HEMA-hydrogel
lens, achieving a release profile of several days [174]. An alternative method has involved, using
vitamin E to essentially create a barrier to improve the release profile of loaded drugs [25,184,185].
The hydrophobic barrier interacts with the drug, which greatly increases the permeation time rather
than simply eluting from the lens. Vitamin E contains a large hydrocarbon side chain and methyl
groups to provide the necessary hydrophobic character. In another experiment by Kim et al., vitamin
E was easily incorporated into commercial silicone-hydrogel lenses such as ACUVUE® , OASYS™,
O2 OPTIX™, and NIGHT&DAY™ [184]. Some of the delivered drugs included cysteamine [186,187]
and pirfenidone [188]. Typically, vitamin E was incorporated into the hydrogel through soaking, and
the hydrophobic character means it is unlikely to leech out, compared with a hydrophilic component
such as PVA. This is a straightforward process that could be adopted into more widespread usage
to improve elution times of drugs from CLs. Although, strictly speaking, there was no fundamental
change to the hydrogel networks, the work is worthy of inclusion given the profound impact on
drug-release profiles. Some examples used straightforward incorporation methods, which could be a
manufacturing consideration.
into the hydrogel through soaking, and the hydrophobic character means it is unlikely to leech out,
compared with a hydrophilic component such as PVA. This is a straightforward process that could
be adopted into more widespread usage to improve elution times of drugs from CLs. Although,
strictly speaking, there was no fundamental change to the hydrogel networks, the work is worthy of
inclusion
Materials given
2019, the profound impact on drug-release profiles. Some examples used straightforward
12, 261 20 of 35
incorporation methods, which could be a manufacturing consideration.

Figure 14.
14.Drug-binding
Drug-bindingand and releasing
releasing mechanism
mechanism for afor a contact
contact lens withlensionic
with ionic
sites sitesthe
within within the
structure.
structure. Reprinted
Reprinted from Journalfrom
of Journal of Controlled
Controlled Release,
Release, 281, Xu, J.;281,
Xue,Xu, J.; Xue,
Y.; Hu, G.; Y.;
Lin,Hu, G.; Lin,
T.; Gou, T.; Gou,
J.; Yin, J.;
T.; He.
Yin,Zhang,
H.; T.; He.Y.; H.;Tang,
Zhang,
X. AY.;comprehensive
Tang, X. A comprehensive reviewlens
review on contact on for
contact lens fordrug
ophthalmic ophthalmic drug
delivery, 97,
Materials 2019, 12,
delivery,
Copyright 97, x FOR PEERpermission
Copyright
2018, with REVIEW
2018, withfrom
permission
Elsevierfrom
[27]. Elsevier [27]. 21 of 36

Figure
Figure 15. Chemical structure
15. Chemical structure ofof beta-cyclodextrin.
beta-cyclodextrin. The
The inner
inner environment
environment of of cyclodextrin
cyclodextrin is
is hydrophobic,
hydrophobic, suitable
suitable for drug-binding,
for drug-binding, whereas
whereas the outside
the outside is hydrophilic,
is hydrophilic, providingproviding
suitable
suitable bioavailability.
bioavailability.

Modern
Modern CL CL materials
materials have
have shown
shown much-improved
much-improved drug drug delivery
delivery capacity
capacity than
than current
current
ophthalmic treatments, such as eye drops. Further modification of the base CL polymer
ophthalmic treatments, such as eye drops. Further modification of the base CL polymer structure is structure
is required
required totoimprove
improvedrug
drugdelivery.
delivery.Molecular
Moleculargrafts,
grafts,particle
particle encapsulation,
encapsulation, and
and soaking
soaking are
are the
the
most
most common methods for modification. Despite evidence of the improving performance of these
common methods for modification. Despite evidence of the improving performance of these
materials,
materials, more
moremust
mustbebe
done
donein order to take
in order thesethese
to take materials to theto
materials point
the of commerciality.
point The biggest
of commerciality. The
biggest barrier to the market is the cost of clinical trials, as well as the manufacturing requirements.
Another note of interest is that most of these successful works have been based on HEMA-hydrogels
[189]. HEMA-based hydrogels have an abundance of easily accessible chemical functional groups for
modification, rather than silicone. In some cases, silicone-based hydrogels were more suitable to host
drugs, such as the vitamin E barrier [27]. This represents an interesting position for CL materials,
Materials 2019, 12, 261 21 of 35

barrier to the market is the cost of clinical trials, as well as the manufacturing requirements. Another
note of interest is that most of these successful works have been based on HEMA-hydrogels [189].
HEMA-based hydrogels have an abundance of easily accessible chemical functional groups for
modification, rather than silicone. In some cases, silicone-based hydrogels were more suitable to
host drugs, such as the vitamin E barrier [27]. This represents an interesting position for CL materials,
where the requirement of increased hydrophilicity for comfort and oxygen permeability has driven
the increased usage of silicone-hydrogels over HEMA-hydrogel lenses. Conventionally, many drugs
are chosen based on a strong hydrophobic character [190]. Development of suitable drug-delivery
lenses will mostly depend on the intended time of treatment, and the length of wear that facilitates
this. In turn, the length of wear will best define what type of CL material should be used and what
modification should support the drug release.

3.2. Emerging CL Materials Technologies

In this section, we will discuss several emerging materials technologies that could be relevant to
future CL materials. Biocompatible materials have become of great interest to the scientific community,
particularly as new materials have been innovated [191–194]. These biocompatible materials could
be an avenue for CL researchers to develop novel materials. The necessity for biocompatibility is an
obvious reason why these materials could be of interest. Two such areas that have seen particular
growth are double-network/interpenetrating hydrogels and pH-responsive polymers. Although
some interest has been expressed in areas such as liquid crystal CLs [195,196], the number of research
publications remains somewhat limited compared to these other technologies. Briefly, the liquid crystal
contact lens is of interest to treating presbyopia, due to the liquid crystal’s on/off character to alter
the lens power in the region of +2.00 D. The liquid crystal lens has anisotropic refractive indexes,
realigning the molecules when a voltage is applied. Commonly, the lens design often involves PMMA
to support the liquid crystal phases [197]. Perhaps the biggest difficulties with these lenses is ensuring
ocular health, comfort, and a power source.
Double-network/interpenetrating hydrogels combine two gels by interconnecting the gel
networks together, resulting in a new gel composite (Figure 16). Essentially, the network of one
gel is intertwined with the other, rather than the formation of a traditional copolymer gel. This is a
subtle, but significant, difference—e.g., a double network gel could be formed by two polymers with
different functional groups, meaning they could not be copolymerized. Figure 16 also shows that
these hydrogels can be formed pre- and post-formation of one gel. Formation of these new materials
has been shown to improve the bioavailability/compatibility of hydrogels [198,199]. Some of the
materials investigated are commonly known CL- or modification-materials, such as HA, chitosan,
thiol-functionalized PEG, poly-2-hydroxyethly acrylate (HEA), and polyacrylamide (PAA). With the
large number of materials used in CL synthesis, this method could produce a unique double-network
contact lens with improved functionality.
Double-network hydrogel formation is fundamentally a chemical technique to improve the bulk
properties of the material. These hydrogels could be manufactured in the same manner as current
CL hydrogels, yet enhance the CL properties. This area is of interest to the CL community; a patent
was assigned to Stanford University in 2010 for interpenetrating polymer-network contact lenses [200].
One example by Yañez et al. used interpenetrating networks composed of HEMA and polyvinyl
pyrrolidone (PVP) to develop new comfortable SCLs [201]. PVP was semi-interpenetrating and leeched
from the lens as a comfort mechanism rather than a true double-network hydrogel. These gels have
been tailored for applications involving tissue engineering, emphasizing the robustness of the gel [202].
The inner eyelid (conjunctiva) and cornea are two different environments sensitive to the properties
of the CL. Castellino et al. combined PDMS-MAA-HEMA to form an interpenetrating hydrogel
network [203]. Their purpose was to form a general bioavailable material, rather than a material for
specific ophthalmic applications. Wang and Li synthesized a double-network hydrogel of TRIS and
HEMA-phosphorylcholine (PC) as a potential ophthalmic material [134]. At higher PC (20%) content,
double-network hydrogel. These gels have been tailored for applications involving tissue
engineering, emphasizing the robustness of the gel [202]. The inner eyelid (conjunctiva) and cornea
are two different environments sensitive to the properties of the CL. Castellino et al. combined
PDMS-MAA-HEMA to form an interpenetrating hydrogel network [203]. Their purpose was to form
a general
Materials bioavailable
2019, 12, 261 material, rather than a material for specific ophthalmic applications. 22 Wang
of 35
and Li synthesized a double-network hydrogel of TRIS and HEMA-phosphorylcholine (PC) as a
potential ophthalmic material [134]. At higher PC (20%) content, the double-network gels had a low
the double-network ◦ ) and a high modulus (7 MPa). These are
water-contact angle gels
(50°)had
anda low water-contact
a high modulus (7angle
MPa).(50These are very attractive qualities for CL
very attractive
hydrogels, qualities
which couldforbe
CLfurther
hydrogels, which could
developed. be further
Other doubledeveloped.
networks Other doublehave
of silicone networks
been
of silicone have been investigated for other research fields, suggesting it could be more
investigated for other research fields, suggesting it could be more widely used for CLs [204–206]. widely used
for CLs [204–206].
These These works incorporated
works incorporated organic components,
organic components, which would
which would be essentialfor
be essential for ocular
ocular
biocompatibility. This type of hydrogel could be the next evolution of contact
biocompatibility. This type of hydrogel could be the next evolution of contact lenses. lenses.

Figure 16. A double-network hydrogel combines the properties of two hydrogels. The gel networks
are interpenetrating, meaning they form a new gel that retains the properties of each individual gel.
Reprinted with permission from John-Wiley and Sons [199].

We have already discussed some of the more popular drug-delivery materials in a previous
section. However, there are new concepts within biocompatible hydrogels as potential drug-delivery
mechanisms [207,208]. Temperature- and pH-responsive polymers are materials that change their
macromolecular conformation when exposed to a specific temperature or acidic/alkaline conditions
(hence, pH-responsive) [209]. For pH-responsive polymers, there are four principal mechanisms
by which the conformation is changed, and this is summarized in Figure 17. The acidic/alkaline
conditions of the body can induce protonation, stripping the coating and conformation changes to
the polymer and allowing release of the drug. As such, they are becoming exciting as drug-delivery
mechanisms within the human body [210]. The concept was recently investigated for drug-delivery
contact lenses [211]. Researchers here used a film of cellulose acetate to deliver betaxolol hydrochloride
over a sustained period. They showed that 25% of the drug was delivered to rabbits in the first 3 h of
use, and 66% had been delivered within 72 h [211]. The cellulose acetate film was attached to a CL
composed of HEMA-NVP-TRIS. Cellulose is a biopolymer and therefore has high biocompatibility,
meaning it is suitable for the ocular environment.
Temperature-responsive polymers, when exposed to sufficient heat, undergo conformation
changes, which allows the release of the embedded/encapsulated drug. Once the conformation change
is complete, the drug will be released in the highly aqueous environment [212,213]. These papers
describe in detail the mechanisms of these polymers [212,213]. This could be relevant to contact
lenses, as typically there is a significant difference between the storage/room temperature and
the eye. A lens composed of such a polymer would undergo a conformation change on insertion
to the eye. This temperature difference could be harnessed for drug-delivery CLs. Polyethylene
glycol (PEG) has seen growth in this area as a block-copolymer graft to other moieties, such as
Materials 2019, 12, 261 23 of 35

poly(N-isopropylacrylamide) (p(NIPAAm)) and HEMA. Silicone rubbers have even been mentioned
as potential drug-delivery vehicles by Fenton et al. [207]. These materials are known for their ocular
compatibility, meaning there is design space to be explored for improved drug-delivery contact lenses.
Jung et al. studied more common contact materials, such as HEMA, due to the ability to modify
conformation with differing conditions, such as nanoparticle loading into the lens [214].
Materials 2019, 12, x FOR PEER REVIEW 24 of 36

Figure 17.
17. Mechanisms
Mechanisms of of action for
for pH-responsive
pH-responsive drug-delivery
drug-delivery polymers.
polymers. Reprinted
Reprinted from
Biomaterials,
Biomaterials, 85,
85, Kanamala,
Kanamala, M.;
M.; Wilson,
Wilson, W.R.;
W.R.; Yang, M.; Palmer, B.D.; Wu, Z. Mechanisms and
biomaterials in pH-responsive
pH-responsive tumour
tumour targeted
targeted drug delivery;
delivery; a review, 152, Copyright 2016, with
permission from Elsevier [210].

interesting new
These emerging materials technologies offer interesting new routes
routes for
for future
future CLCL development.
development.
We have provided some approaches, such as novel materials in the form of
We have provided some approaches, such as novel materials in the form of liquid crystals, liquid crystals, or evolving
or
the CL material
evolving the CL through methods
material through suchmethods
as double-network hydrogels. In addition,
such as double-network temperature-
hydrogels. and
In addition,
pH-responsive
temperature- and polymers are growing
pH-responsive drug-delivery
polymers vehicles,drug-delivery
are growing but have not yet been widely
vehicles, explored
but have for
not yet
CLs. What
been widelyis explored
encouraging is theWhat
for CLs. fact that many of these
is encouraging is methods involve
the fact that manymany of the
of these same materials
methods involve
used for
many current
of the sameCLs, meaning
materials used adapting to CLs
for current CLs,ismeaning
a clear possibility
adapting to in CLs
the near future.
is a clear However,
possibility in
despite these encouraging signs, there are significant challenges for the ocular environment,
the near future. However, despite these encouraging signs, there are significant challenges for the which
remain environment,
ocular prominent given the aging
which remain population
prominent worldwide
given the[215].
agingThis includes specific
population worldwideaspects, such
[215]. as
This
anti-fungal
includes drug aspects,
specific delivery,such
which are not yet ready
as anti-fungal for commercial
drug delivery, which arespecifications
not yet ready [216].
for The biggest
commercial
challenge for these
specifications [216].materials is the
The biggest efforts infor
challenge other CLmaterials
these research, is
asthe
previously
efforts indiscussed.
other CL research, as
previously discussed.

4. Manufacturing Perspectives
The final part of developing a CL is how the new material will be manufactured. New
technologies have emerged to enhance CL properties, such as plasma processing, to introduce
hydrophilicity to silicone lenses. CL manufacturing is an ever-evolving area, with manufacturers
constantly improving their methods. It is probably fair to say there is much the public does not know
Materials 2019, 12, 261 24 of 35

4. Manufacturing Perspectives
The final part of developing a CL is how the new material will be manufactured. New technologies
have emerged to enhance CL properties, such as plasma processing, to introduce hydrophilicity to
silicone lenses. CL manufacturing is an ever-evolving area, with manufacturers constantly improving
their methods. It is probably fair to say there is much the public does not know about the specific
CL manufacturing methodologies. This includes operating conditions, speed of lathes, tip-edge
Materials 2019, 12, x FOR PEER REVIEW 25 of 36
parameters, and exact chemical recipes, amongst a huge number of parameters. For researchers,
this can be can
researchers a difficult area tothe
still analyze evaluate,
products given
fromsuch lack of information.
manufacturers to help shapeHowever, researchers
the direction of theircan
still analyze the products from manufacturers to help shape the direction
research. There is literature concerning the differences in the mechanical properties of common of their research. There is
literature concerning
HEMA-derived hydrogelthe differences
lenses based in the on
mechanical properties of technique
the manufacturing common HEMA-derived
(Figure 18) [49]. hydrogel
The
lenses based on the manufacturing technique (Figure 18) [49]. The
polymerization and manufacturing method were responsible for the differences in the hydrogel polymerization and manufacturing
method were
properties. responsible
Improving thefor the differences
polymerization in the
steps hydrogel
during properties. Improving
manufacturing could improve the polymerization
the properties
steps during manufacturing could improve the properties
of the lens materials. The manufacturing- or process-driven development is likely of the lens materials. The manufacturing-
pursued for
economical or environmental reasons, or both. For example, Nelfilcon A PVA lenses use waterorasboth.
or process-driven development is likely pursued for economical or environmental reasons, the
For example,
solvent, whichNelfilcon
is muchA easierPVA lenses use water
to handle thanasorganic
the solvent, which
solvents andis much
does easier to handle
not require than
further
organic solvents
processing and does
[16]. Here, we not
willrequire
discuss further
someprocessing
specialist [16]. Here, we will
manufacturing discuss some
techniques seen specialist
in other
manufacturing techniques seen in other applications of optics that could
applications of optics that could be used for CL manufacturing. We also discuss some aspects of be used for CL manufacturing.
We also discusssuch
manufacturing, someasaspects
molding, of manufacturing,
and the materials such
thatashavemolding, and the materials
been investigated in recent thatliterature.
have been
investigated in recent literature.
Materials are an important consideration for the molding processes, i.e., both cast- and
MaterialsThe
spin-molding. areinteraction
an important betweenconsideration for theand
the mold surface molding
polymerprocesses,
solution willi.e.,affect
boththe cast- and
surface
spin-molding. The interaction between the mold surface and polymer
finish of the CL. Some examples of common molding materials are polypropylene [42] and quartz solution will affect the surface
finish
[16]. of the CL. Some
Polypropylene examples
is useful dueoftocommon
the ease molding
of handling materials
and high are melt
polypropylene
temperatures.[42] Theand polymer
quartz [16]. is
Polypropylene is useful due to the ease of handling and high
hydrophobic, meaning manufacturers choose this with the intent that the contact lens will not melt temperatures. The polymer
is hydrophobic,
adhere strongly meaning
to the mold manufacturers
surface on choose this with the
polymerization intent that the
(particularly contact lens
hydrophilic will not
materials).
adhere strongly
Similarly, quartzto the2)mold
(SiO surface on polymerization
has non-sticking qualities that are (particularly
useful forhydrophilic
manufacturing materials).
lenses. Similarly,
This is a
quartz (SiO 2 ) has non-sticking qualities that are useful for manufacturing
practical consideration to reduce defect occurrence in the final CLs. The recent patent literature lenses. This is a practical
has
consideration
many examplestoof reduce
the new defect occurrence
materials beinginconsidered
the final CLs. as aThelensrecent
mold patent
materialliterature
[217–220]. has These
many
examples
patents areofassigned
the newtomaterials being considered
CLs manufacturers, showing as the
a lens mold material
commercial [217–220].
implications These patents
of improving this
are assigned to CLs manufacturers, showing the commercial
aspect of manufacturing. Some of the mold materials include alicyclic polymers implications of improving this aspector of
manufacturing. Some of the mold materials include alicyclic polymers
polyoxymethylene, which are non-polar and polar, respectively. The mold material can influence the or polyoxymethylene, which
are non-polar
adhesion to the andmold,
polar,which,
respectively.
in turn,Thecould
mold influence
material can theinfluence
resultingthe adhesion to
wettability the mold, of
properties which,
the
in turn,
hydrogels. could influence the resulting wettability properties of the hydrogels.

Figure 18. Tensile

Figure 18. Tensileand
andYoung’s
Young’s modulus
modulus datadata for HEMA-based
for HEMA-based hydrogel
hydrogel lenses produced
lenses produced by
by different
different manufacturing methods. Reprinted with permission from John-Wiley
manufacturing methods. Reprinted with permission from John-Wiley and Sons [49].and Sons [49].

Ultra-precision-
Ultra-precision-and
andnano-manufacturing
nano-manufacturingisisan anarea
areaof
ofresearch
researchthat
thatcould
couldbebeapplied
appliedto
to CLs
CLs to
to
enhance
enhance the
the physical
physical and
and optical
optical properties
properties of
of the
the material
material [221–223].
[221–223]. These
These techniques
techniques have
have been
been
successfully implemented in a number of areas, including biomedical device manufacturing, optics,
and more [224]. Ultra-precision lathes are now used in the production of specialty CLs to obtain
nanometer control of the surface, which can control the wettability characteristics of polymers [225]
and glass surfaces [226]. However, to date, this has not been extensively applied to contact lenses, or
at least cannot be seen in the published literature. However, the control of wettability is possible by
Materials 2019, 12, 261 25 of 35

successfully implemented in a number of areas, including biomedical device manufacturing, optics,

and more [224]. Ultra-precision lathes are now used in the production of specialty CLs to obtain
nanometer control of the surface, which can control the wettability characteristics of polymers [225]
and glass surfaces [226]. However, to date, this has not been extensively applied to contact lenses, or
at least cannot be seen in the published literature. However, the control of wettability is possible by
using machining techniques [227]. Freeform optics are a special type of optical lenses with irregular
contouring on a non-symmetrical surface. Improvements in optical performance have seen their use in
applications relating to imaging, illumination, and aerospace interests [228,229]. This is an increasingly
important area of precision manufacturing, requiring consideration of the design, as well as machining
and evaluation aspects [230]. Furthermore, servo-control machining could be feasible to fabricate
freeform optical CLs for specialty applications, such as myopia control. Fast servo-manufacturing of
freeform optics has even been shown to be feasible on polymers such as polystyrene [231]. This suggests
that the use of a similar technique could be employed on a pre-hydrated CL material. The usage of
such precision manufacturing techniques to intraocular lens manufacturing was also reported [232].
All of these techniques are subject to the effect which the resulting material will have on the ocular
environment, such as the effect on the tear film, protein deposition, optical properties, etc. Finally, there
is a cost component to manufacturing in a commercial space that would also need to be considered.

5. Conclusions
The purpose of this review was to bring together state-of-the-art research on contact lenses and
their modification. Modern CL research aims to better deliver ophthalmic treatments or improve
existing issues with contact lenses. Overall, modern CL materials are an evolution of the well-known
lens materials based on HEMA and silicone hydrogels. These hydrogels grafted or incorporated
various bioavailable components, such as PEG, HA, chitosan, β-cyclodextrin, cellulose, and other
moieties. These biomaterials are very biocompatible due to their inherent chemistry. The biomaterials
field is exciting and dynamic, where new and improved biocompatible, drug-delivering materials are
constantly being developed. One of the biggest hurdles to overcome is the cost and practicality of
incorporating such species to a new lens. We highlighted some emerging fields related to CLs due
to the materials involved or which have only recently been applied to CLs. The application of new
manufacturing methods can offer other solutions to specific challenges for CLs: new mold materials,
surface contouring, etc. CL materials are now resilient and modifiable, and are thus suitable for these
improving manufacturing processes. Advances in precision manufacturing, such as the production of
freeform optics or modification of surface properties to improve wettability could be applied to future
CLs. In summary, future CL materials will continue to push the boundaries of the biocompatibility
and materials sciences to better tailor to the needs of a growing CL-using population.

Author Contributions: C.S.A.M. conducted the literature survey and prepared the manuscript. F.F. designed the
manuscript structure and finalized the paper.
Funding: This work was supported by the Science Foundation Ireland (Nos. 15/RP/B3208 & 16RC3872) and the
National Natural Science Foundation of China (Nos. 51320105009 & 61635008).
Acknowledgments: In this section you can acknowledge any support given which is not covered by the author
contribution or funding sections. This may include administrative and technical support, or donations in kind
(e.g., materials used for experiments).
Conflicts of Interest: The authors declare no conflict of interest.

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