polymers

Review
Implantable Polymeric Drug Delivery Devices:
Classification, Manufacture, Materials, and
Clinical Applications
Sarah A. Stewart , Juan Domínguez-Robles, Ryan F. Donnelly and Eneko Larrañeta *
School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK;
sstewart35@[Link] (S.A.S.); [Link]@[Link] (J.D.-R.); [Link]@[Link] (R.F.D.)
* Correspondence: [Link]@[Link]; Tel.: +44-(0)28-9097-2360




Received: 8 November 2018; Accepted: 10 December 2018; Published: 12 December 2018


Abstract: The oral route is a popular and convenient means of drug delivery. However, despite its
advantages, it also has challenges. Many drugs are not suitable for oral delivery due to: first pass
metabolism; less than ideal properties; and side-effects of treatment. Additionally, oral delivery relies
heavily on patient compliance. Implantable drug delivery devices are an alternative system that
can achieve effective delivery with lower drug concentrations, and as a result, minimise side-effects
whilst increasing patient compliance. This article gives an overview of classification of these drug
delivery devices; the mechanism of drug release; the materials used for manufacture; the various
methods of manufacture; and examples of clinical applications of implantable drug delivery devices.

Keywords: implants; drug delivery; design; manufacture

1. Introduction
The oral route remains the most popular and convenient method of drug delivery, with many
advantages. However, along with other common routes such as transdermal, or intravenous (IV)
injection, it also presents a number of disadvantages and challenges. Many drugs are not suitable
for delivery via the oral route. This may be as a result of: drug degradation in the acidic conditions
of the stomach or alkaline conditions in the intestine [1]; first pass metabolism; or compliance issues.
In addition, many newly discovered drug compounds do not possess the ideal chemical properties for
oral delivery.
IV delivery may overcome some of the issues associated with oral delivery such as: first pass
metabolism; degradation in the stomach; or poor solubility and bioavailability. However, this route
is not without disadvantages. A healthcare professional will be required for administration, and
there may be sterility or specific storage issues. It is also an invasive delivery technique which
may be unsuitable for those patients who suffer from needle phobia. The transdermal route offers
advantages such as: avoidance of first pass metabolism; avoidance of gastro-intestinal degradation;
and non-invasiveness [2]. However, it also has a number of issues which prevent it becoming the ideal
drug delivery route. Very few drug compounds possess the specific properties such as: low molecular
weight; a Log P value between 1 and 3; good solubility; and high partition coefficient [2], that are
required to pass through the skins outer barrier, the stratum corneum, without help from additional
methods such as the use of iontophoresis or microneedles.
Therefore, there is a need for novel drug delivery systems to improve delivery of existing drug
compounds, and to allow delivery of newly discovered drugs with less than ideal properties for oral
drug delivery [3]. The development of new drug delivery systems should aim to optimise effectiveness
and tolerability of drug compounds, whilst ideally simplifying their administration [4].

Polymers 2018, 10, 1379; doi:10.3390/polym10121379 [Link]/journal/polymers

Polymers 2018, 10, 1379 2 of 24

A promising alternative delivery method is the use of polymeric implantable devices to deliver
drug compounds. Implantable drug delivery systems allow targeted and localised drug delivery
and may achieve a therapeutic effect with lower concentrations of drug [3,5,6]. As a result, they
may minimise potential side-effects of therapy, while offering the opportunity for increased patient
compliance [7]. This type of system also has the potential to deliver drugs which would normally
be unsuitable orally [6], because it avoids first pass metabolism and chemical degradation in the
stomach and intestine, thus, increasing bioavailability [7]. Implantable devices will require a healthcare
professional for insertion, and the insertion itself will be a relatively invasive process. However, unlike
other methods this will only be required once. The prolonged drug delivery that will be achieved
without the reliance on patient compliance overcomes these disadvantages. Another advantage of
implantable drug delivery devices is that they offer the opportunity for early removal if adverse effects
require termination of treatment [8,9].

2. Implantable Polymeric Drug Delivery Device Classification

Implantable drug delivery device classification is not a straightforward task as there are a number
of complex implants that will fall into hybrid categories. Nevertheless, implantable drug delivery
devices can be broadly classified in two main groups: passive implants and active implants. The
first group includes two main types of implants: biodegradable and non-biodegradable implants.
On the other hand, active systems rely on energy dependent methods that provide the driving force
to control drug release. The second group includes devices such as osmotic pressure gradients and
electromechanical drives. However, the latter are normally metallic implants and this review focuses
on polymeric devices. Consequently, they will not be covered in this review.

2.1. Passive Polymeric Implants

These are normally relatively simple devices with no moving parts, they rely on passive diffusion
for drug release. They are generally made of drugs packed within a biocompatible polymer molecule.
Several parameters such as: drug type/concentration, polymer type, implant design and surface
properties can be modified to control the release profile. Passive implants can be classified in two main
categories: non-biodegradable and biodegradable systems.

2.1.1. Non-Biodegradable Polymeric Implantable Systems

Non-biodegradable implants are commonly prepared using polymers such as silicones,
poly(urethanes), poly(acrylates) or copolymers such as poly(ethyelene vinyl acetate) [10–14]. This type
of device can be monolithic or reservoir type implant, as shown in Figure 1. Monolithic type implants
are made from a polymer matrix in which the drug is homogeneously dispersed [15]. On the other
hand, reservoir-type implants contain a compact drug core covered by a permeable non-biodegradable
membrane. The membrane thickness and the permeability of the drug through the membrane will
govern the release kinetics [16].
Non-biodegradable implantable drug delivery systems have been extensively used for
contraceptive delivery [15]. These devices are structurally resilient and robust over their lifetime.
Accordingly, the main drawback of non-biodegradable implants is that after depleting their drug
load, they need to be removed. The materials used to prepare these devices show good long-term
biocompatibility, but sometimes they can cause infections, tissue damage or cosmetic disfigurement [15].
Accordingly, once all the drug has been released, they are normally extracted to prevent any
adverse effects.
Polymers 2018, 10, 1379 3 of 24
Polymers 2018, 10, x FOR PEER REVIEW 3 of 24

Figure 1. An
Figure 1. An illustration
illustration of
of reservoir
reservoir and
and monolithic
monolithic type
type implants.
implants.
2.1.2. Biodegradable Polymeric Implants
Non-biodegradable implantable drug delivery systems have been extensively used for
Biodegradable
contraceptive delivery implants were devices
[15]. These developed to overcomeresilient
are structurally the drawbacks
and robust of non-biodegradable
over their lifetime.
implants.
Accordingly, These devices
the main are made
drawback using polymers or
of non-biodegradable block copolymers
implants that can be
is that after depleting broken
their drug
down into need
load, they smaller fragments
to be removed. that
Thewill be subsequently
materials used to prepareexcreted or absorbed
these devices show by the body
good [17,18].
long-term
Normally they arebut
biocompatibility, made using polymers
sometimes such as
they can cause poly(caprolactone)
infections, tissue damage(PCL), poly(lactic
or cosmetic acid) (PLA)
disfigurement
or poly(lactic-co-glycolic
[15]. Accordingly, once all acid)
the(PLGA)
drug has[15].
beenThese materials
released, theyhave been extensively
are normally studied
extracted and their
to prevent any
degradation
adverse effects. kinetics can be easily tuned to adjust the drug release rate. The main advantage of this
type of implant is that they do not need to be extracted after implantation, as they will be degraded by
2.1.2.
the Biodegradable
body of the [Link]
They can Implants
be manufactured using the same designs described in the previous
section: monolithic implants and reservoir-type implants [15]. One drawback of this particular type
Biodegradable implants were developed to overcome the drawbacks of non-biodegradable
of device is that they are more complex to develop than the non-biodegradable ones. The range of
implants. These devices are made using polymers or block copolymers that can be broken down into
potential materials that can be used is reduced, and the regulatory requirements are stricter as the
smaller fragments that will be subsequently excreted or absorbed by the body [17,18]. Normally they
material will be left behind in the body. Finally, the degradation of the polymeric matrix is the main
are made using polymers such as poly(caprolactone) (PCL), poly(lactic acid) (PLA) or poly(lactic-co-
driving force for drug release. However, this can be highly variable in each patient.
glycolic acid) (PLGA) [15]. These materials have been extensively studied and their degradation
kinetics
2.2. can be
Dynamic or easily
Activetuned to adjust
Polymeric the drug release rate. The main advantage of this type of implant
Implants
is that they do not need to be extracted after implantation, as they will be degraded by the body of
These types
the patient. Theyofcan implants have a positive
be manufactured usingdriving
the same force to control
designs the release
described in theofprevious
drugs from the
section:
device
monolithic[15]. implants
Therefore, they
and present a higher
reservoir-type degree
implants of One
[15]. control of drugof
drawback release. However,
this particular dueoftodevice
type their
complexity they present higher development costs [15]. The majority of the implants
is that they are more complex to develop than the non-biodegradable ones. The range of potential in this category
are electronic
materials thatsystems made
can be used is of metallicand
reduced, materials. However,
the regulatory to remain within
requirements the scope
are stricter as theof this article,
material will
only polymeric implants will be described. Dynamic drug delivery implants are
be left behind in the body. Finally, the degradation of the polymeric matrix is the main driving forcemainly pump type
implants. The main
for drug release. type ofthis
However, polymeric activevariable
can be highly implants in are
each osmotic
[Link]. This type of device is
formed mainly by a semipermeable membrane that surrounds a drug reservoir [15], as shown in
Figure 2. Theor
2.2. Dynamic membrane shouldImplants
Active Polymeric have an orifice that will allow drug release. Osmotic gradients will
allow a steady inflow of fluid within the implant. This process will lead to an increase in the pressure
These types of implants have a positive driving force to control the release of drugs from the
within the implant that will force drug release trough the orifice. This design allows constant drug
device [15]. Therefore, they present a higher degree of control of drug release. However, due to their
release (zero order kinetics). This type of device allows a favourable release rate but the drug loading
complexity they present higher development costs [15]. The majority of the implants in this category
is limited [15].
are electronic systems made of metallic materials. However, to remain within the scope of this article,
only polymeric implants will be described. Dynamic drug delivery implants are mainly pump type
implants. The main type of polymeric active implants are osmotic pumps. This type of device is
formed mainly by a semipermeable membrane that surrounds a drug reservoir [15], as shown in
Figure 2. The membrane should have an orifice that will allow drug release. Osmotic gradients will
 Polymers 2018, 10, x FOR PEER REVIEW 4 of 24

allow a steady inflow of fluid within the implant. This process will lead to an increase in the pressure
within the implant that will force drug release trough the orifice. This design allows constant drug
release (zero order kinetics). This type of device allows a favourable release rate but the drug
Polymers 2018, 10, 1379
loading
4 of 24
is limited [15].

Figure
Figure 2. [Link]
An illustration
of anof an osmotic
osmotic implantable
implantable drugdrug delivery
delivery systems.
systems.

3. Mechanism of Drug
3. Mechanism Release
of Drug fromfrom
Release Implantable Polymeric
Implantable DrugDrug
Polymeric Delivery Systems
Delivery Systems
Mechanisms
Mechanisms of drug release
of drug fromfrom
release implantable
implantable systems
systemsare mainly
are mainlyclassified into into
classified fourfour
groups:groups:
matrix degradation; controlled swelling; osmotic pumping; and passive
matrix degradation; controlled swelling; osmotic pumping; and passive diffusion [19]. For systems diffusion [19]. For systems
based on controlled
based on controlled swelling, solvent
swelling, penetration
solvent penetration into into
the matrix of the
the matrix of device controls
the device the rate
controls of of
the rate
release. This is usually much slower than diffusion of the drugs, and will, therefore,
release. This is usually much slower than diffusion of the drugs, and will, therefore, lead to a lower lead to a lower
release rate rate
release [15]. [15].
Although
Although the diffusion
the diffusion fromfrom swollen matrices
swollen is mainly
matrices is mainlyresponsible for the
responsible for drug
the drug
release, matrix degradation could also contribute in the effectiveness of
release, matrix degradation could also contribute in the effectiveness of these systems [20]. these systems [20].
On theOnother hand,
the other osmotic
hand, pumping
osmotic pumping and passive
and passive diffusion mechanisms
diffusion mechanisms of drug delivery
of drug are the
delivery are the
mostmost
promising
promisingfor linear delivery
for linear of drugs.
delivery In this
of drugs. In case, the amount
this case, of released
the amount drugdrug
of released is proportional
is proportional
to the
tosquare
the squareroot root
of theofrelease [Link].
the release
Osmosis is the overall movement
Osmosis is the overall movement of water
of waterfromfroma dilute solution
a dilute to a more
solution to a moreconcentrated
concentratedsolution
solution
through a partially permeable membrane, and it causes a hydrostatic pressure
through a partially permeable membrane, and it causes a hydrostatic pressure difference between difference between the the
two compartments [21]. Osmotic pumping is a phenomenon that utilizes
two compartments [21]. Osmotic pumping is a phenomenon that utilizes the abovementioned the abovementioned concept
to adjust
conceptthe todelivery
adjust rate
the of drugs in
delivery ratedefined
of drugs conditions.
in defined In conditions.
this case, osmotic
In thispressure, caused
case, osmotic by
pressure,
watercaused
absorption, drives the transport of the drug. Moreover, implantable drug
by water absorption, drives the transport of the drug. Moreover, implantable drug delivery delivery devices based
on this phenomenon
devices based onwillthisdemonstrate
phenomenona will constant release rate
demonstrate [22]. release rate [22].
a constant
Diffusion is a process
Diffusion by which
is a process molecules
by which molecules transfer spontaneously
transfer spontaneously fromfromone region to another
one region to anotherto to
equilibrate chemical potential or thermodynamic activity. In this mechanism,
equilibrate chemical potential or thermodynamic activity. In this mechanism, migrating molecules migrating molecules are
usually known as
are usually the diffusants
known or permeants,
as the diffusants or permeants, and the membrane
and the membraneor matrix in which
or matrix the diffusant
in which the diffusant
migrates is called the diffusional barrier. Additionally, the external phase
migrates is called the diffusional barrier. Additionally, the external phase is termed medium. is termed medium. The The
driving force of this drug release mechanism is the concentration gradient or
driving force of this drug release mechanism is the concentration gradient or profile of the diffusant profile of the diffusant
within the diffusional
within barrier
the diffusional [23]. In
barrier drug
[23]. In delivery
drug delivery systems mediated
systems by swelling,
mediated osmoticosmotic
by swelling, pressure or
pressure
passive diffusion, the release kinetics of drugs will depend on key factors such
or passive diffusion, the release kinetics of drugs will depend on key factors such as: the solubility as: the solubility and
diffusion coefficientcoefficient
and diffusion of the molecule
of the in the polymer;
molecule in the the drug load;
polymer; and the
the drug in vivo
load; and degradation rate of
the in vivo degradation
the polymer
rate of the [24].
polymer [24].

3.1. Mechanism of Drug Release from Non-Biodegradable Implants

3.1. Mechanism of Drug Release from Non-Biodegradable Implants
Non-degradable polymers have been widely applied in the fabrication of transdermal films
Non-degradable polymers have been widely applied in the fabrication of transdermal films or
or implant devices, among other biomedical applications [25]. Representative polymers for the
implant devices, among other biomedical applications [25]. Representative polymers for the
development of these devices include poly(urethanes), silicone, and poly(ethylene vinyl acetate),
development of these devices include poly(urethanes), silicone, and poly(ethylene vinyl acetate),
which will be discussed later in this article. Although multiple types of non-degradable implants are
which will be discussed later in this article. Although multiple types of non-degradable implants are
commercially available, membrane enclosed reservoir and matrix-controlled systems (as described
commercially available, membrane enclosed reservoir and matrix-controlled systems (as described
previously) are by far the most commonly used [19]. For these non-degradable implants passive
previously) are by far the most commonly used [19]. For these non-degradable implants passive
diffusion is the main driver of solute transport.
diffusion is the main driver of solute transport.
Reservoir-type systems separate a drug compartment from a polymer membrane that presents a
diffusional barrier to yield drug flux [23]. These systems have the benefit of maintaining a constant
release rate that is not affected by concentration gradient, but most likely is related to the thickness
and permeability of the rate-controlling polymeric membrane (zero-order release) [26]. In contrast,
matrix-type systems consist of a rate-controlling medium such as a polymer with drug uniformly
Polymers 2018, 10, 1379 5 of 24

dissolved or dispersed in it, and typically, a half order drug release corresponds to desorption from the
preloaded matrix [23]. In the latter systems, the drug release is mainly mediated by Fickian diffusion,
which is affected by concentration gradient, diffusion distance, and the degree of swelling [27,28].
These systems provide a slow diffusion of the drug through the polymeric material, helping to sustain
the drug release. Nevertheless, the release kinetics of matrix-type systems are dependent on the
volume fraction of the agent in the matrix, meaning that the release from these systems are directly
proportional to the encapsulated drug within the matrix [15].

3.2. Mechanism of Drug Release from Biodegradable Implants

Implantable drug delivery devices generally consist of a drug reservoir surrounded by a polymer
or a drug polymer mixture [6]. When inserted into the desired area of the body, the drug will be
released at a pre-determined rate as the polymer degrades. Drug release from a reservoir system is
controlled by the rate of polymer degradation or drug dissolution into, and then diffusion through, the
polymer wall, or a combination of both. Drug release from a drug polymer mixture is controlled by
diffusion, swelling or erosion. The release of drug from the system will be dependent on: the solubility
and permeability of the drug in the polymer; the drug load; and the in vivo degradation rate of the
polymer [6].
Degradation of the polymer and subsequent drug release may occur through one, or a combination
of processes including: hydrolysis, in which bonds, e.g., ester bonds, in the polymer backbone are
broken down [29]; enzyme degradation, in which hydrolytically susceptible bonds, e.g., amide bonds,
demonstrate degradation in the presence of a catalyst [29]; oxidation [30]; and physical degradation, in
which bonds are broken as a result of physical forces such as swelling or mechanical loading [30]. The
degradation time of polymers can vary extensively depending on features such as polymer molecular
weight and surface properties [29]. This will, in turn, affect the release of any drug contained within
a formulation. In addition, degradation will also be dependent on in vivo factors such as: pH; and
temperature [6]. Therefore, the in vivo degradation time of any polymer needs to be fully characterised.

4. Polymers Used for Implantable Polymeric Drug Delivery Devices

Polymers used to manufacture implantable drug delivery devices can be divided into two
categories: biodegradable and non-biodegradable [6]. Major disadvantages of non-biodegradable
implants include the need for surgical removal, or accumulation of polymer in the body after
use [6]. The surgical removal of non-biodegradable implants is often more traumatic than their
insertion [31], as established in a study by Odom et al. [32]. The study investigated the removal of
the non-biodegradable contraceptive implant, Nexplanon® , and concluded that a multidisciplinary
care team and the expertise of a peripheral nerve surgeon may be beneficial to the successful removal
of such implants [32]. Alternatively, biodegradable polymers offer the significant advantage of not
having to be surgically removed after use. They are designed to degrade naturally to products that
can be excreted easily by the body after they have achieved their purpose [29]. The need for surgical
removal of an implant made from non-biodegradable polymers complicates its use.
Polymers have been widely investigated for use in tissue engineering and drug delivery. Both
natural and synthetic polymers have been investigated [33]. Synthetic polymers are generally
biologically inert, have predictable chemical and physical properties, and don’t have the same
batch to batch inconsistency that occurs with natural polymers [33,34]. The biodegradability and
biocompatibility of any material will be critical when designing a drug delivery system [35]. Any
materials used must be fully biocompatible, and any changes in polymer properties that develop as it
degrades must be fully investigated and characterised [29].
Ideally, any chosen biodegradable polymer should be: highly reproducible; easily metabolised and
excreted by physiological pathways; degradable to non-toxic products; and free from an inflammatory
response in vivo [29,36]. A single ideal polymer does not exist, and the choice of polymer will be
 Polymers 2018, 10, x FOR PEER REVIEW 6 of 24
Polymers 2018, 10, x FOR PEER REVIEW 6 of 24

materials used must be fully biocompatible, and any changes in polymer properties that develop as
materials used must be fully biocompatible, and any changes in polymer properties that develop as
it degrades must be fully investigated and characterised [29].
it degrades must be fully investigated and characterised [29].
Ideally, any chosen biodegradable polymer should be: highly reproducible; easily metabolised
Ideally,10,any
Polymers
chosen biodegradable polymer should be: highly reproducible; easily metabolised
1379 6 of 24an
and 2018,
excreted by physiological pathways; degradable to non-toxic products; and free from
and excreted by physiological pathways; degradable to non-toxic products; and free from an
inflammatory response in vivo [29,36]. A single ideal polymer does not exist, and the choice of
inflammatory response in vivo [29,36]. A single ideal polymer does not exist, and the choice of
polymer on
dependent willthebemechanism
dependent and
on the mechanism and rateand
of release desired, of
and a combination of
polymer will be dependent on therate of releaseand
mechanism desired, a combination
rate of release desired, and polymers may be
a combination of
polymers
required may be required to produce the characteristics required.
polymerstomayproduce the characteristics
be required required.
to produce the characteristics required.
4.1.
4.1. Biodegradable
Biodegradable Polymers
Polymers
4.1. Biodegradable Polymers
4.1.1.
4.1.1. Thermoplastic
Thermoplastic Aliphatic
Aliphatic Polyesters
Polyesters
4.1.1. Thermoplastic Aliphatic Polyesters
Thermoplastic
Thermoplastic aliphatic
aliphatic poly(esters)
poly(esters) including:
including: poly(lactic
poly(lactic acid) poly(glycolic
acid) (PLA), (PLA), poly(glycolic acid)
acid) (PGA),
Thermoplastic aliphatic poly(esters) including: poly(lactic acid) (PLA), poly(glycolic acid)
and(PGA), and poly(lactic-co-glycolic
poly(lactic-co-glycolic acid) (PLGA)
acid) (PLGA) (Figure(Figure
3) have3) been
have been
widelywidely investigated
investigated duedue
to to their
their
(PGA), and poly(lactic-co-glycolic acid) (PLGA) (Figure 3) have been widely investigated due to their
favourable characteristics such as biodegradability, biocompatibility and mechanical
favourable characteristics such as biodegradability, biocompatibility and mechanical strength [37–39]. strength [37–
favourable characteristics such as biodegradability, biocompatibility and mechanical strength [37–
39]. polymers
These These polymers have previously
have previously been successfully
been successfully used in nanoparticle
used in nanoparticle based drugbased drugsystems
delivery delivery
39]. These polymers have previously been successfully used in nanoparticle based drug delivery
andsystems andmicroparticle
solid and solid and microparticle
parenteralparenteral implants
implants [38]. [38]. Degradation
Degradation periods for periods
these for these polymers
polymers range
systems and solid and microparticle parenteral implants [38]. Degradation periods for these polymers
range
from onefrom one to
month month
over to
sixover six months
months [40]. mechanisms
[40]. The The mechanisms of degradation
of degradation for for
PLA,PLA,
PGAPGA andand
range from one month to over six months [40]. The mechanisms of degradation for PLA, PGA and
PLGA
PLGA areare shown
shown in in Figure
Figure 4. 4. Degradation
Degradation rate
rate is is affected
affected byby factors
factors such
such as as hydrophilicity,
hydrophilicity, glass
glass
PLGA are shown in Figure 4. Degradation rate is affected by factors such as hydrophilicity, glass
transition
transition temperature
temperature andand molecular
molecular weight
weight andand environmental
environmental conditions
conditions such
such as as temperature
temperature andand
transition temperature and molecular weight and environmental conditions such as temperature and
pHpH [34,39,40].
[34,39,40].
pH [34,39,40].

PLA PGA PLGA PCL

PLA PGA PLGA PCL

Figure AnAn
3. 3.
Figure illustration of of
illustration thethe
chemical structures
chemical of: of:
structures poly(lactic acid)
poly(lactic (PLA);
acid) poly(glycolic
(PLA); acid)
poly(glycolic acid)
Figure 3. An illustration of the chemical structures of: poly(lactic acid) (PLA); poly(glycolic acid)
(PGA); poly(lactic-co-glycolic
(PGA); acid)
poly(lactic-co-glycolic (PLGA);
acid) andand
(PLGA); poly(caprolactone)
poly(caprolactone)(PCL).
(PCL).
(PGA); poly(lactic-co-glycolic acid) (PLGA); and poly(caprolactone) (PCL).

O O
O Degradation O
O Degradation O
HO O H HO O H
HO H HO HO H
CH3 H2O2 CH3
CH3 CH3
PLA Lactic acid
PLA Lactic acid
O O
O Degradation O
O
HO O H Degradation HO O
O
H
HO H HO HO H
H 2O2
PGA Glycolic acid
PGA Glycolic acid
C O O O
C H3 H3 O Degradation O O
HO O
HO O O H Degradation
H H2O H O
O
O H+ + HO O O H
O H2O HO H HO H
O CH3
O CH3
PLGA Glycolic acid Lactic acid
PLGA Glycolic acid Lactic acid
Figure 4. An
Figure illustration
4. An of the
illustration mechanisms
of the mechanisms of degradation of poly(lactic
of degradation acid)
of poly(lactic (PLA);
acid) poly(glycolic
(PLA); poly(glycolic
Figure 4. An illustration of the mechanisms of degradation of poly(lactic acid) (PLA); poly(glycolic
acid) (PGA);
acid) and
(PGA); andpoly(lactic-co-glycolic acid)
poly(lactic-co-glycolic (PLGA).
acid) (PLGA).
acid) (PGA); and poly(lactic-co-glycolic acid) (PLGA).
Poly(lactic acid)
Poly(lactic acid) (PLA) is a biodegradable and bioresorbable polymer that can be obtained
through the polymerisation of lactic acid obtained from natural feedstock (i.e., Corn starch rice or
potatoes, among others) with promising properties for medical applications [41–44]. PLA shows similar
mechanical properties to other synthetic polymers, such as polypropylene, while presenting lower cost,
higher abundance and biodegradability [42]. Moreover, PLA is semipermeable to oxygen and water
making this polymer more inclined to biodegradation than other biomedical polymers [43,45,46]. The
US Food and Drug Administration (FDA) approved the use of PLA in direct contact with biological
Polymers 2018, 10, 1379 7 of 24

fluids as it is a generally recognised as safe (GRAS) material [41]. PLA can be processed using a
wide variety of techniques due to its great thermal processability [44]. Accordingly, it can be used in
extrusion, film casting, blow moulding or fibre spinning processes, among others [44]. This is a great
advantage over other biomaterials such as poly(ethylene glycol). Finally, PLA production requires
between 25% and 55% less fossil energy than petroleum-based polymers [44]. Accordingly, PLA is the
second most traded polymer in the world [43].
At room temperature PLA is a white powder showing melting and glass transition temperatures
of around 175 and 55 ◦ C, respectively [44]. High molecular weight PLA shows similar properties to
polystyrene. Due to the existence of two stereoisomers of lactic acid (D and L), PLA can be made using
both types of monomers [44]. PLA prepared using D-lactic acid, PDLA, is a crystalline material due to
its regular chain structure [44]. On the other hand, PLA made using L-lactic acid, PLLA, will have a
hemi-crystalline structure [44]. Additionally, PLA with a mixture of both can be prepared (PDLLA) to
obtain an amorphous polymer [44]. All these polymers are soluble in a wide variety of organic solvents
such as: benzene, chloroform, acetonitrile, tetrahydrofuran or dioxane [44]. Due to the hydrophobic
nature of PLA, this polymer is insoluble in ethanol, methanol and aliphatic hydrocarbons [44].
The biodegradability and mechanical properties of PLA are influenced by the chirality of the
monomer. It has been established that D and D/L forms of PLA degrade more rapidly than the L form,
as the latter has a higher crystallinity [42,47–50]. Increasing the surface area-to-volume ratio or the
porosity of the polymer will improve the rate of degradation of the polymer [51].
The main PLA mechanism of degradation is the hydrolysis of the ester bond backbone [52].
Therefore, the products obtained in the degradation are lactic acid or lactic acid oligomers. Interestingly,
the degradation is catalysed by the newly-formed terminal carboxylic acid groups at the ends of the
PLA chains [53]. Temperature and pH influence the degradability of the material. PLA showed
higher degradation rates at physiological temperature than at 25 ◦ C. Furthermore, at lower pH the
degradation of this polymer is much slower than at physiological pH [54].
In addition to PLA hydrolysis, this polymer can be enzymatically biodegraded. After implantation
of the polymer in the body immune cells will be directed to the implantation site. These cells will
secrete enzymes, including lactate dehydrogenase and acid phosphatase that will contribute to PLA
degradation [55].

Poly(glycolic acid)
Poly(glycolic acid) (PGA) is a polyester made by polymerisation of glycolic acid units. It was one
of the first biodegradable polymers used for biomedical applications. PGA is a polymer that exists in
only one highly crystalline form [47,56]. It exhibits excellent mechanical properties (greater than those
of PLA), and a melting point greater than 200 ◦ C [33]. Biodegradable sutures made from PGA have
been successfully used, for example, Dexon® [33]. PGA exhibits a quick degradation profile and it
is insoluble in many common solvents. Accordingly, this polymer has not been used alone for drug
delivery purposes. PGA undergoes bulk degradation via scission of its ester backbone to form glycine,
which is excreted in the urine or via the citric acid cycle [33,47]. However, the acidic by-products of
PGA can cause inflammation in the surrounding tissues [47] and limit the potential use of PGA as a
lone polymer.

Poly(lactic-co-glycolic acid)
Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable and biocompatible copolymer of PLA
and PGA [47]. PLGA degrades in the body via hydrolysis to form lactic acid and glycolic acid [5,38].
PLGA, therefore, presents itself as an interesting candidate as a polymer for implantable drug delivery
devices [40]. It is possible to modify the physical properties of the polymer by altering the polymer
molecular weight and ratio of lactide to glycolide [40]. The presence of side methyl groups within
PLA make the copolymer more hydrophobic. Thus, PLGA copolymers with high PLA content show
higher hydrophobicity and, consequently, a slower degradation rate. Advantages of PLGA include: an
Polymers 2018, 10, 1379 8 of 24

increased degradation rate in comparison to PLLA, but decreased in comparison to PDLA; and a lack
of acidic by-products produced upon degradation [47]. The monomer composition and the molecular
weight of the PLGA molecules have a direct influence in the crystallinity of the polymer. Similar to
the previously described polymers, the mechanical properties and the degradation rates are strongly
influenced by the degree of crystallinity of the polymer. A higher PGA content within PLGA leads
to a lower crystallinity degree and a higher rate of hydration/hydrolysis. PLGA containing 50:50 of
PLA:PGA shows the highest degradation rates. PLGA copolymers present Tg values above 37 ◦ C,
thus, exhibiting a fairly rigid chain structure, ideal for implant manufacturing. Finally, PLGA can be
processed into a wide variety of shapes and sizes due to its solubility in common solvents such as
tetrahydrofuran, acetone, ethyl acetate or chlorinated solvents.

Poly(caprolactone)
Poly(caprolactone) (PCL) is a promising candidate for use in polymeric implants due to its
biocompatibility, biodegradability, non-toxicity, and relatively low cost [31,33]. It has FDA approval
for use in medical applications [57], and it has already been successfully incorporated into materials
used for sutures and wound dressings [58]. The presence of unstable aliphatic ester bonds allows
the polymer to biodegrade by a mixture of random hydrolysis of ester bonds and bulk degradation
pathways [33,38,59,60]. PCL degrades to form products that are metabolised via the tricarboxylic acid
cycle or are renally eliminated [61]. PCL is a hydrophobic, semi-crystalline polymer [59]. Its low
melting point (55–60 ◦ C [33]), good solubility, and good compatibility with other materials make it a
promising candidate for use in sub-dermal implants [59].
PCL has a relatively long degradation time, ranging from several months to years, but this is
dependent on internal factors, such as its molecular weight [59], and degradation conditions such as:
temperature; pH; and presence of enzymes. Degradation time increases as molecular weight increases.
As molecular weight increases, the chain length and, therefore, the number of ester bonds that need to
be cleaved to create water soluble monomers and oligomers also increases [59]. The slow degradation
of PCL is due to its hydrophobic nature, which does not allow water penetration [1,60]. The rate of
hydrolysis of ester linkages, therefore, will be affected by factors which increase the penetration of
water into the polymer [57].
PCL degrades slower than other polymers such as PGA, PLA and PLGA [61]. However, PCL is a
relatively low-cost polymer, which may make it more commercially viable for use in a product. As a
result of this comparatively long degradation time, co-polymers of PCL have been investigated [33].
PCL has been shown to be compatible and forms miscible blends [33] with other polymers. This
provides the opportunity to create polymer blends with unique properties and degradation kinetics.
For example, copolymerisation with hydrophilic monomers can increase the rate of degradation [61,62].
Poly(ethylene glycol) (PEG), with its inherent hydrophilicity and lack of immunogenicity and toxicity, is
a promising candidate for copolymerisation with PCL to form a material with improved hydrophilicity
and biodegradability [4]. PCL-PEG copolymers have been shown to have increased biocompatibility
when compared to the PCL homopolymer [4]. The addition of PEG to PCL is likely to reduce the
degradation time of the polymer by allowing increased water penetration and, therefore, rate of
hydrolysis. The polymer’s glass transition temperature (Tg ) and crystallinity will also affect the ability
of water to penetrate the polymer [57]. A high Tg will correlate to limited molecular motion, low free
volume within the polymer and, therefore, reduced availability for water penetration. Reduction of Tg
and crystallinity will accelerate hydrolytic degradation. Addition of PEG to form PCL-PEG blends
is likely to create a blend with lower Tg and crystallinity and, therefore, reduced degradation time.
The rate of degradation can also be altered by copolymerisation with other lactones, glycolides or
lactides [59]. PCL, therefore, is a highly diverse material and has the potential to be a suitable polymer
in the development of implantable drug delivery systems.
penetration. Reduction of Tg and crystallinity will accelerate hydrolytic degradation. Addition of PEG
to form PCL-PEG blends is likely to create a blend with lower Tg and crystallinity and, therefore,
reduced degradation time. The rate of degradation can also be altered by copolymerisation with other
lactones, glycolides or lactides [59]. PCL, therefore, is a highly diverse material and has the potential
to be a suitable polymer in the development of implantable drug delivery systems.
Polymers 2018, 10, 1379 9 of 24

Other Biodegradable Polymers

OtherPLA,
Biodegradable
PGA, PLGA Polymers
and PCL are the most commonly used biodegradable polymers for biomedical
applications
PLA, PGA, because
PLGAof andtheir
PCLbiocompatibility, mechanical
are the most commonly used strength and ease
biodegradable of formulation
polymers [63].
for biomedical
However, numerous less commonly used biodegradable polymers for drug delivery exist
applications because of their biocompatibility, mechanical strength and ease of formulation [63]. including:
poly(amides),
However, poly(anhydrides),
numerous less commonly poly(phosphazenes)
used biodegradable andpolymers
poly(dioxanone)
for drug[34,64].
delivery Poly(anhydrides)
exist including:
have a low hydrolytic stability resulting in rapid degradation rates, making them suitable
poly(amides), poly(anhydrides), poly(phosphazenes) and poly(dioxanone) [34,64]. Poly(anhydrides) for use in
have a low hydrolytic stability resulting in rapid degradation rates, making them suitable for can
short-term controlled delivery systems [65]. Poly(phosphazenes) have a degradation rate that use be
in
finely tuned by appropriate substitution with specific chemical groups and use of these polymers
short-term controlled delivery systems [65]. Poly(phosphazenes) have a degradation rate that can be has
been investigated
finely for skeletal
tuned by appropriate tissue regeneration
substitution andchemical
with specific drug delivery
groups[65].
andPoly(dioxanone), like PCL,
use of these polymers has
been investigated for skeletal tissue regeneration and drug delivery [65]. Poly(dioxanone), like[66].
is a polylactone that has been used for purposes such as drug delivery, and tissue engineering PCL,
is a polylactone that has been used for purposes such as drug delivery, and tissue engineering [66].
4.2. Non-Biodegradable Polymers
4.2. Non-Biodegradable Polymers
4.2.1. Poly(siloxanes)
4.2.1. Poly(siloxanes)
Poly(siloxanes) or silicones are organosilicon polymeric materials composed of silicon and
oxygenPoly(siloxanes) or silicones
atoms [67]. Figure 5 showsare theorganosilicon
chemical structure polymeric
of thismaterials composed
type of polymer. of silicon
Lateral groupsandcan
oxygen
be methyl,atoms
vinyl[67].
or Figure
phenyl 5groups
shows[67].
the chemical
These groupsstructure of this type
will influence theofproperties
polymer. of Lateral groups
the polymer.
can be methyl, have
Poly(siloxanes) vinylbeen
or phenyl groups
extensively used[67]. These groups
in medicine due towill
the influence the properties
unique combination of the
of thermal
polymer. Poly(siloxanes) have been extensively used in medicine due
stability, biocompatibility, chemical inertness and elastomeric properties [67]. The siliconesto the unique combination of
thermal
commonly stability,
used forbiocompatibility,
medical devices chemical inertness
are vulcanised at and
roomelastomeric
temperature. properties
They are[67]. The silicones
prepared using a
two-component
commonly used forpoly(dimethylsiloxanes)
medical devices are vulcanised(PDMS) in at the
room presence of a catalyst
temperature. They are(platinum
prepared usingbased
acompound)
two-component [67,68]. The final material is formed
poly(dimethylsiloxanes) (PDMS)via in antheaddition
presencehydrosilation
of a catalyst reaction
(platinum [67]. An
based
alternative method
compound) [67,68]. to Theobtain silicones isforformed
final material medicalvia applications
an addition is the using linear
hydrosilation reactionPDMS
[67]. with
An
hydroxyl terminal
alternative method groups
to obtain [69]. This linear
silicones polymerapplications
for medical is cross-linkedis thewith lowlinear
using molecular
PDMSweightwith
tetra(alkyloxysilane)
hydroxyl terminal groupsusing stannous
[69]. This octoate
linearcatalyst.
polymer is cross-linked with low molecular weight
Non-biodegradable
tetra(alkyloxysilane) usingpolymers
stannous show
octoatedifferent
catalyst. drug release mechanisms than biodegradable
polymers [26]. The latter relies
Non-biodegradable polymerson two maindifferent
show factors: the
drug diffusion
releaseofmechanisms
the drug from the biodegradable
than matrix and the
degradation
polymers of the
[26]. Thematrix.
latter This
reliestopic
on twois discussed in a previous
main factors: sectionofofthe
the diffusion thisdrug
[Link]
However, non-
the matrix
biodegradable
and polymers
the degradation of thesuch as PDMS
matrix. rely is
This topic solely on theindiffusion
discussed a previous of section
the drug offrom a PDMS
this work. matrix
However,
or through a PDMS polymers
non-biodegradable membranesuch [26,67]. PDMS rely
as PDMS has been
solelyused as a diffusion
on the rate controlling
of the membrane
drug from in a wide
a PDMS
varietyor
matrix ofthrough
drug delivery
a PDMS devices
membrane[26,67]. Therefore,
[26,67]. PDMS thehasdiffusivity
been usedofas the drugcontrolling
a rate through the PDMS is
membrane
crucial
in a wideto variety
control ofthe dosedelivery
drug [26]. PDMS is prepared
devices as a crosslinked
[26,67]. Therefore, [Link]
the diffusivity theadrug
resultthrough
of this, the
the
crosslinking
PDMS density
is crucial will influence
to control the dose [26].waterPDMSuptake of the material
is prepared and the diffusivity
as a crosslinked network. As ofathe drug
result of [26].
this,
Accordingly,
the crosslinking these parameters
density should
will influence be optimised
water uptake of the in material
order to and
obtain the required
the diffusivity drug
of the release
drug [26].
profile.
Accordingly, these parameters should be optimised in order to obtain the required drug release profile.

Figure 5. An illustration of the chemical structure of poly(siloxane).

Figure 5. An illustration of the chemical structure of poly(siloxane).
4.2.2. Poly(ethylene-vinyl acetate)
Poly(ethylene-vinyl acetate) (PEVA) is a thermoplastic copolymer of ethylene and vinyl
acetate [70]. The units of these two monomers are randomly distributed through the polymer chain [71].
Figure 6 shows the structure of this polymer. The ratio between the two monomers will strongly
influence the properties of the polymer [71]. The vinyl acetate (VA) content will impact on the melting
point, crystallinity and stiffness of the material [71]. The crystallinity of PEVA decreases when the
content of VA increases [71]. Accordingly, the final properties of the material can be tailored by
optimising the monomers ratio. The biocompatibility of PEVA has been extensively demonstrated
 Poly(ethylene-vinyl acetate) (PEVA) is a thermoplastic copolymer of ethylene and vinyl acetate
[70]. The units of these two monomers are randomly distributed through the polymer chain [71].
Figure 6 shows the structure of this polymer. The ratio between the two monomers will strongly
influence the properties of the polymer [71]. The vinyl acetate (VA) content will impact on the melting
point,
Polymerscrystallinity
2018, 10, 1379 and stiffness of the material [71]. The crystallinity of PEVA decreases when the
10 of 24
content of VA increases [71]. Accordingly, the final properties of the material can be tailored by
optimising the monomers ratio. The biocompatibility of PEVA has been extensively demonstrated
and it
and it was
was approved
approved by by the
the FDA
FDA [70].
[70]. Additionally,
Additionally, it
it is
is on
on the
the inactive
inactive ingredients
ingredients list
list for
for non-drug
non-drug
products [70]. Finally, PEVA is a non-degradable/resorbable material
products [70]. Finally, PEVA is a non-degradable/resorbable material [13]. [13].

Figure 6.
Figure Anillustration
6. An illustration of
of the
the chemical
chemical structure
structure of
of poly(ethylene-vinyl
poly(ethylene-vinyl acetate)
acetate) (PEVA).
(PEVA).

PEVA has
PEVA has been
been extensively
extensivelyused
usedforfordrug
drug delivery
delivery applications
applications [13,70].
[13,70]. As PEVA
As PEVA is a
is a non-
non-degradable
degradable material,
material, the diffusion
the diffusion of the
of the drug drug
from the from
matrixthe matrix
will governwill
the govern the release
release mechanism
mechanism [26]. However, PEVA can be used in reservoir type systems
[26]. However, PEVA can be used in reservoir type systems as rate controlling membrane as rate controlling
[13,70].
membrane [13,70]. Increasing the crystallinity reduce the diffusivity of the polymer. Accordingly,
Increasing the crystallinity reduce the diffusivity of the polymer. Accordingly, by changing the vinyl by
changing the vinyl
acetate/ethylene acetate/ethylene
ratio ratiorelease
can tailor the drug can tailor the drug
profile [26]. release profile [26].
4.3. Other Polymers
4.3. Other Polymers
4.3.1. Poly(urethanes)
4.3.1. Poly(urethanes)
Polyurethanes (PU) are a broad family of polymers obtained from the reaction of diisocyanates
with polyols using a(PU)
Polyurethanes are a as
catalyst, broad
seenfamily of polymers
in Figure obtained
7 [72]. This type offrom the reaction
polymer presents ofadiisocyanates
wide variety
with polyols using
of structures a catalyst, as
and properties, asseen in Figure
different 7 [72]. This type ofcan
polyols/diiscyanates polymer
be used presents a wide variety
to synthesize of
this type
structures and properties, as different polyols/diiscyanates can be used
of polymer [72]. The diisocyanates contain two –N=C=O groups per molecule [73] and they can to synthesize this type of
polymer [72].mono/polycyclic
be aliphatic, The diisocyanates or contain
aromatic two –N=C=O
[72]. The usegroups per molecule
of different isocyanates[73]will
andinfluence
they can the
be
aliphatic,
propertiesmono/polycyclic or aromatic
of the resulting polymer [72]. The isocyanates
[72]. Aromatic use of different isocyanates
will lead will materials
to more rigid influencewith
the
properties of the resulting polymer [72]. Aromatic isocyanates will lead to more rigid
lower oxidative stabilities [73]. Aliphatic isocyanates will present better oxidative stability [73]. materials with
lower
On theoxidative
other hand,stabilities [73]. polyols
different Aliphaticcan isocyanates
be used will present
to obtain PUbetter
suchoxidative stabilitypolyester
as: polyesters, [73]. On
the other hand, different polyols can be used to obtain PU such as: polyesters,
polyols, polycaprolactones, polycarbonates and polyethers [72]. Finally, there is an alternative polyester polyols,
type
polycaprolactones, polycarbonates and polyethers [72]. Finally, there is
of compound added during PU synthesis that changes the final properties of the material: chain an alternative type of
compound addedThese
extenders [72,74]. during PU synthesis
molecules that changes
are normally short-chainthediols
finalsuch
properties of the material:
as 1,4-butanediol. chain
PU polymers
extenders [72,74]. These molecules are normally short-chain diols such
are normally formed by hard segments and soft segments [72,75]. The soft segments are dependent as 1,4-butanediol. PU
polymers are normally formed by hard segments and soft segments [72,75]. The
on the diol molecule chain and provide flexibility to the material [72,75]. On the other hand, the soft segments are
dependent on the diol molecule chain and provide flexibility to the material [72,75]. On the other
hard segments are formed by the reaction between the chain extenders and the diisocyanates and
hand, the hard segments are formed by the reaction between the chain extenders and the
they provide extra strength to the material [72,75]. Due to the variety of the parameters that can
diisocyanates and they provide extra strength to the material [72,75]. Due to the variety of the
be modified, PUs are a broad family of polymers [76]. Biodegradable PU can be prepared by using
parameters that can be modified, PUs are a broad family of polymers [76]. Biodegradable PU can be
biodegradable polyols such as poly(caprolactone) or poly(ethylene glycol) [77]. On the other hand,
prepared by using biodegradable polyols such as poly(caprolactone) or poly(ethylene glycol) [77].
PU can be prepared to obtain PU based rubbers with similar properties and behaviour to PDMS [67].
OnPolymers 2018, 10,
the other x FORPU
hand, PEER
canREVIEW
be prepared to obtain PU based rubbers with similar properties11and of 24
Accordingly, this type of polymer is versatile.
behaviour to PDMS [67]. Accordingly, this type of polymer is versatile.

+
Diol Diisocyanate

PU
Figure 7. An illustration of the chemical structure of poly(urethane) (PU).
Figure 7. An illustration of the chemical structure of poly(urethane) (PU).

4.3.2. Natural Polymers

In addition to the biopolymers, such as the abovementioned PLA, there a few natural polymers
which also represent a promising class of materials with a wide range of applications, including use
in implantable devices. These natural polymers include, cellulose, chitosan, silk and others naturally
 PU

Polymers 2018, 10, 1379Figure 7. An illustration of the chemical structure of poly(urethane) (PU). 11 of 24

4.3.2. Natural Polymers

4.3.2. Natural Polymers
In addition to the biopolymers, such as the abovementioned PLA, there a few natural polymers
In addition
which also to thea biopolymers,
represent such
promising class of as the abovementioned
materials PLA, of
with a wide range there a few natural
applications, polymers
including use
which also represent a promising class of materials with a wide range of applications,
in implantable devices. These natural polymers include, cellulose, chitosan, silk and others naturallyincluding
use in implantable
derived devices.
proteins. These Thesepresent
materials naturalcertain
polymers include,compared
advantages cellulose,tochitosan, silk and
the traditional others
materials
naturally derived proteins. These materials present certain advantages compared to
(metals and ceramics) or synthetic polymers, such as biocompatibility, biodegradation and non- the traditional
materials (metals
cytotoxicity, and
which ceramics)
make or synthetic
them ideal polymers,
to be used such as drug
in implantable biocompatibility, biodegradation
delivery devices [78]. and
non-cytotoxicity, which make them ideal to be used in implantable drug delivery devices [78].
Cellulose
Cellulose
Cellulose is the most abundant organic compound in the world and it is mostly produced by
Cellulose is the most abundant organic compound in the world and it is mostly produced by plants.
plants. Cellulose is a natural linear polymer (polysaccharide), whose structure consists of long
Cellulose is a natural linear polymer (polysaccharide), whose structure consists of long polymer chains
polymer chains of repeating β-D-glucopyranose units that are covalently linked through acetal
of repeating β-D-glucopyranose units that are covalently linked through acetal functions between the
functions between the C1 carbon atom and the equatorial −OH group of C4 (β-1,4-glycosidic bonds)
C1 carbon atom and the equatorial −OH group of C4 (β-1,4-glycosidic bonds) (Figure 8) [79].
(Figure 8) [79].

structure of
Figure 8. An illustration of the chemical structure of cellulose
cellulose [80].
[80].

Cellulose
Cellulose and
and its
its many
many derivatives,
derivatives,including
includingcellulose
celluloseethers/esters,
ethers/esters, micro/nano-sized
micro/nano-sized cellulose
products,
products,bacterial
bacterialcellulose
cellulose(BC), have
(BC), beenbeen
have widely studied
widely for many
studied for applications [81–85]. For
many applications instance,
[81–85]. For
Modulevsky et al. used the native hypanthium tissue of apples to create
instance, Modulevsky et al. used the native hypanthium tissue of apples to create implantable implantable cellulose
scaffolds
cellulose [84]. This [84].
scaffolds approach is complementary
This approach to the use of
is complementary to BC
the which
use of has been successfully
BC which employed
has been successfully
for the development
employed of implantable
for the development materials.
of implantable Due to Due
materials. its nanostructure and properties,
to its nanostructure BC isBC
and properties, a
is a promising
promising candidate
candidate forgreat
for a a great range
range of medical
of medical [Link]
applications. BCfibres
fibreshave
haveaahigh
high degree
degree of
crystallinity and their endotoxin level is within the suitable suitable range
range ofof endotoxin
endotoxin values
values forfor implants
implants
the FDA,
based on the FDA, which
which means
means theythey could
could be
be used
used safely
safely in
in intravenous
intravenous applications.
applications. BC has beenbeen
possess more
shown to possess more suitable
suitable properties
properties than
than plant-derived
plant-derived cellulose or nanocellulose
nanocellulose and it is is
mainly due to its biosynthesis procedure [81,83]. [81,83]. It is important, however,
however, to to note
note that plant-derived
polymers are much
polymers much moremorecost
costeffective
effectivetotoproduce
produceand andareare
extremely
extremely straightforward
straightforward to prepare for
to prepare
implantation.
for implantation.
Additionally, cellulose
Additionally, cellulose nanocrystals
nanocrystals (CNCs) and cellulose nanofibrils (CNFs) are also currently
under intense investigation for the the development
development of of biomedical
biomedical applications
applications such
such as:
as: implants, tissue
engineering, drug delivery, antibacterial/antimicrobial, cardiovascular and wound healing [85].
Indeed, it can be observed how the number of publications in the period 2000–2013 on cellulose
materials for such applications has been gradually increasing [85].

Chitosan
Chitosan is the second most abundant polymer, after cellulose. It is a cationic polysaccharide
produced by deacetylation of chitin, which is found in the exoskeletons of insects, the cell walls of
fungi, and certain hard structures in invertebrates and fish [78,86]. This natural polymer is structurally
composed of N-acetyl-D-glucosamine and D-glucosamine units with one amino (NH2 ) group and two
hydroxyl (–OH) groups in each repeating glycosidic units [87]. The structure of chitosan is shown in
Figure 9. Due to its properties, it has been extensively used in a large amount of applications ranging
from medical to industrial areas, including application in implantable drug delivery devices [87–89].
produced by deacetylation of chitin, which is found in the exoskeletons of insects, the cell walls of
fungi,
fungi, and
and certain
certain hard
hard structures
structures in in invertebrates
invertebrates and
and fish
fish [78,86].
[78,86]. This
This natural
natural polymer
polymer is is
structurally composed of N-acetyl-
structurally composed of N-acetyl-D-glucosamine and D-glucosamine units with one amino (NH22))
D -glucosamine and D -glucosamine units with one amino (NH
group
group and
and twotwo hydroxyl
hydroxyl (–OH)
(–OH) groups
groups in in each
each repeating
repeating glycosidic
glycosidic units
units [87].
[87]. The
The structure
structure of
of
chitosan is shown in Figure 9. Due to its properties, it has been extensively used in a large
chitosan is shown in Figure 9. Due to its properties, it has been extensively used in a large amount of amount of
Polymers 2018, 10, 1379
applications 12 of 24
applications ranging
ranging from
from medical
medical toto industrial
industrial areas,
areas, including
including application
application in
in implantable
implantable drug
drug
delivery
delivery devices.
devices. [87–89].
[87–89].

Figure
Figure 9.
Figure 9. An
9. An illustration
An illustration of
illustration of the
of the chemical
the chemical structures
chemical structures of
structures of Chitin
Chitin and
and Chitosan
Chitosan [90].
[90].

Silk
Silk
Silk
Silk is another
Silk another commonly natural natural polymer used used to develop
develop implantable drug drug deliverydevices.
devices.
Silk is
is another commonly
commonly natural polymer polymer used to to develop implantable
implantable drug delivery
delivery devices.
It is assumed
It assumed that the the largest producer
producer of silksilk in nature
nature is the Bombyx mori [91].
the silkworm, Bombyx [91]. Raw silk
silk
It is
is assumed that that the largest
largest producer of of silk in
in nature is is the silkworm,
silkworm, Bombyx mori mori [91]. Raw
Raw silk
coming
coming from a silkworm is composed of fibroid in the core; silk fibroin, which is the structural protein
coming fromfrom aa silkworm
silkworm is is composed
composed of of fibroid
fibroid in
in the
the core;
core; silk
silk fibroin,
fibroin, which
which isis the
the structural
structural protein
protein
produced in
produced in the
the posterior
posterior region
region ofof the Bombyx mori
the Bombyx mori gland;
gland; and
and aa glue-like
glue-like coating
coating consisting
consisting ofof sericin
sericin
produced in the posterior region of the Bombyx mori gland; and a glue-like coating consisting of sericin
proteins [78].
proteins
proteins [78].
[78].
The structure of
The of silk fibroin
fibroin has been
been well-characterised, and and some recent
recent studies suggest
suggest that
The structure
structure of silk
silk fibroin hashas been well-characterised,
well-characterised, and some some recent studies
studies suggest thatthat
this
this structural protein shows exceptional physicochemical and biological properties desirable for drug
this structural protein shows exceptional physicochemical and biological properties desirable for
structural protein shows exceptional physicochemical and biological properties desirable for
delivery applications
drug [91]. Structurally, silk fibroinfibroin
forms a β-sheet structure in which hydrogen bonds
drug delivery
delivery applications
applications [91].
[91]. Structurally,
Structurally, silk
silk fibroin forms
forms aa β-sheet
β-sheet structure
structure inin which
which hydrogen
hydrogen
and van dervan
bonds Waals interactions generate a structure that is thermodynamically stable (Figure (Figure
10) [78].
bonds and and van der der Waals
Waals interactions
interactions generate
generate aa structure
structure that
that is
is thermodynamically
thermodynamically stable stable (Figure
Therefore,
10) silk is a versatile natural polymer that can bethatused for be various drug delivery applications
10) [78].
[78]. Therefore,
Therefore, silksilk is
is aa versatile
versatile natural
natural polymer
polymer that can can be used
used for
for various
various drug
drug delivery
delivery
including:
applications injectable particles [92,93], bioadhesives [94,95], hydrogels [96,97], reservoirs and scaffold
applications including:
including: injectable
injectable particles
particles [92,93],
[92,93], bioadhesives
bioadhesives [94,95],
[94,95], hydrogels
hydrogels [96,97],
[96,97], reservoirs
reservoirs
implants [98,99].
and
and scaffold
scaffold implants
implants [98,99].
[98,99].

Figure
Figure 10. An illustration of (a) aa three chain silk sequence composed of carbon (gray), nitrogen (blue),
Figure 10.
10. An
Anillustration
illustration of
of(a)
(a) athree
threechain
chainsilk
silksequence
sequencecomposed
composedof ofcarbon
carbon(gray),
(gray),nitrogen
nitrogen(blue),
(blue),
oxygen
oxygen (red) and hydrogen (white); (b) 3-dimensional β-sheet of silk. Reproduced with permission
oxygen (red)
(red) and hydrogen (white);
and hydrogen (white); (b)
(b) 3-dimensional
3-dimensional β-sheet
β-sheet of silk. Reproduced
of silk. Reproduced with
with permission
permission
from
from [100].
[100].

Nowadays, other naturally derived proteins such as: collagen, gelatin, albumin, elastin and milk
proteins have led the research community to offer an interesting alternative to PLGA-based systems
and are being extensively investigated for their potential use in drug delivery applications [101].

5. Methods of Implant Manufacture

A number of factors need to be considered when choosing a manufacturing method for production
of an implantable drug delivery devices including: cost, efficiency and differences in properties of
the produced implants. Implants can be manufactured using a variety of techniques including:
compression, solvent casting, hot melt extrusion, injection moulding or more recently 3D printing.
Thermoplastic polymers such as PLA or PLGA can produce implants using techniques such as: hot
moulding, injection moulding, compression or extrusion [7]. Implants prepared by different techniques
are unlikely to form polymers with exactly the same microporous structure and will degrade at different
Polymers 2018, 10, 1379 13 of 24

rates and, therefore, will have different in vitro and in vivo release profiles [7]. Fialho et al. compared
the process of hot moulding and compression as techniques to make intra-ocular implants, and found
that, the manufacturing technique significantly influenced the polymer degradation and, therefore,
drug release from the resulting implants [7], with compressed implants showing an increased rate of
drug release than their moulded counterparts.

5.1. Compression
One advantage of compression as a manufacturing technique is the lack of requirement for use
of heat or solvents, making it a suitable method for manufacture of implants containing heat or
solvent sensitive compounds such a proteins or peptides [102]. However, implants produced using
this technique often show a faster release profile than observed with other manufacturing techniques,
and drug release may need to be prolonged using additional methods, such as coating the implant.
In addition, as shown by Fialho et al., implants produced by compression had an irregular surface with
many pores and channels [7], which may lead to irregular release from implant produced in this way.

5.2. Solvent Casting

In the solvent casting method, the polymer is first dissolved in a suitable solvent, then the resulting
solution is cast into a mould and the solvent is removed by evaporation [40]. Implants produced by
this method often result in films or laminar implants [103–105]. A disadvantage of this method is
the need for large amounts of organic solvent, which can have an effect on the stability of drugs and
toxicity, and may give rise to environmental concerns [40].

5.3. Hot Melt Extrusion

Hot melt extrusion is the process of melting, mixing, and forcing a polymer through a small
orifice called a die [40]. A prerequisite for the use of melt extrusion is that the polymers used must
be thermoplastic [106]. Aliphatic poly(esters) including PLA, PGA and PLGA are all thermoplastic
and, therefore, suitable for processing by this method [106]. This method offers the advantage of
requiring no solvents; however, it can cause the degradation of thermally labile drugs [40]. This
does not preclude its use in manufacture of implants containing thermally labile drugs. Repka et al.
found that it was possible to successfully incorporate hydrocortisone, a thermally labile drug, into
hydroxypropyl cellulose (HPC) films produced by melt extrusion [107]. Products such as Zoladex® ,
Depot-Profact® and Implanon® are manufactured in this way using melt extrusion [7,106]. Extrusion
can be performed as a continuous process, which allows high throughput rates [106].

5.4. Injection Moulding

Thermoplastic polymers such as PLGA or PLA can be manufactured into implants using injection
moulding. The polymer is heated, injected into a specific mould and allowed to solidify. As a result of
the high heat applied, a decrease in the molecular weight of the polymers can be seen. The effect of
manufacturing using extrusion versus injection moulding on the degradation properties of a polymeric
matrix of PLA was investigated by Rothen-Weinhold et al. [108]. It was found that the molecular weight
and polydispersity was reduced by both techniques, but the decrease was more pronounced with
injection moulding. As a result, extruded implants degraded more rapidly than those manufactured
using injection moulding [108].

5.5. 3D Printing
3D printing technology is currently used to produce dental implants, protheses and orthopaedic
implants [109]. It is a cost-effective, reproducible and highly adaptable method and could be very
promising in the manufacture of implantable drug delivery devices [109]. 3D printing could be used to
manufacture the biodegradable implant structure, which would subsequently be filled with the drug,
Polymers 2018, 10, 1379 14 of 24

with release from the implant controlled by degradation of the implant structure, or rate-controlling
membranes covering orifices in the implant. 3D printing is an extremely promising technique and
would be particularly valuable in the rapid production of prototypes for investigation. Its suitability
for use as a mass production manufacturing technique is still uncertain. However, the suitability of
3D printing for the manufacture of commercial products took a step forward in 2015 after the FDA
approval of a 3D-printed drug product [110].

6. Implantable Polymeric Device Design

Implantable polymeric rods are the most widely used design [5,111]. Other implantable drug
delivery device designs exist, for example, those which are formed in situ as a result of a polymer
undergoing a sol-gel transition, for example Oncogel® [112]. Newer polymeric designs under
investigation include: PCL film implant devices, as shown in Figure 11A [9]; and silicone rods
with dissolving membranes [113]. Advances in manufacturing techniques may result in the creation
of more complex implant designs to allow very specific drug release targeted to a specific disease or
individual patient requirements.
As the majority of implantable drug delivery devices are rod shaped and are designed to be
delivery sub-cutaneously or intramuscularly, the most common method of implantation is via a needle
or surgical implantation. Some implants, for example Nexplanon® , are inserted via a specifically
designed
Polymers 2018,applicator device
10, x FOR PEER that comes with the product, as shown in Figure 11C,D. Other sites
REVIEW 15 of for
24
implantation include: intravaginal, intraocular, intra-vesicular, and intra-tumoral.

A B C

Figure 11. Images showing: (A) prototype PCL film implants [9]; (B) Gliadel Wafers® , reproduced
with permission from [114] (C) Nexplanon® applicator device and (D) insertion of Nexplanon® using
Figure 11. Images
its applicator showing:
device, (A) prototype
reproduced PCL film
with permission implants
from [115]. [9]; (B) Gliadel Wafers , reproduced
®

with permission from [114] (C) Nexplanon applicator device and (D) insertion of Nexplanon® using
®

7. Current Therapeutic
its applicator Applications
device, reproduced with permission from [115].
Implantable drug delivery devices have the potential to be used for a wide variety of clinical
7. Current Therapeutic Applications
applications in areas including, but not limited to: women’s health, oncology, ocular disease, pain
Implantable
management, drug delivery
infectious disease devices have
and central the potential
nervous system to be used[6,15].
disorders for a Examples
wide variety of clinical
of implantable
applications
drug delivery indevices
areas including,
for each ofbut notareas
these limited
are to: women’s health,
summarised oncology,
in Tables 1–4. ocular disease, pain
management,
Women’s infectious
health is onedisease and implantable
area where central nervous system disorders
drug delivery devices have [6,15].
had aExamples of
large impact,
implantable
particularly drug delivery
in their use for devices for eachInof1990,
contraception. these areas are
Norplant summarised
became the firstinimplantable
Tables 1–[Link]
Women’s
device health is one
to be approved. area where
Implantable implantable
long drug deliveryhave
acting contraceptives devices
beenhave hadtoa be
shown large
theimpact,
among
particularly in their use for contraception. In 1990, Norplant became the first implantable
contraceptive device to be approved. Implantable long acting contraceptives have been shown to be
the among the most effective form of contraception, with an annual pregnancy rate of less than 1%
for women using these methods [116,117]. Table 1 shows examples of implantable drug delivery
devices for use in women’s health.
Polymers 2018, 10, 1379 15 of 24

the most effective form of contraception, with an annual pregnancy rate of less than 1% for women
using these methods [116,117]. Table 1 shows examples of implantable drug delivery devices for use
in women’s health.

Table 1. Examples of implantable drug delivery devices used in the area of women’s health.

Product Name Implant Type Material Drug Delivered Indication References

Norplant®
Sub-cutaneous Silicone Levonorgestrel Contraception [118,119]
Jadelle®
Menopausal
Estring® Intra-vaginal Silicone Estradiol [120]
symptoms
Etonogestrel,
Nuvaring® Intra-vaginal PEVA Contraception [121,122]
Ethinyl estradiol
Implanon®
Sub-cutaneous PEVA Etonogestrel Contraception [123,124]
Nexplanon®

Systemic delivery of chemotherapeutic agents is the most common route of administration.

However, it often involves delivery of the agents at their maximum tolerated dose which can lead to
severe side-effects such as neutropenia and cardiomyopathy [125]. Implantation of a drug delivery
device close to the site of action may allow reduced systemic exposure and as a result reduce the
damage caused to healthy tissue. Some examples of implantable drug delivery devices for the treatment
of cancer are shown in Table 2.

Table 2. Examples of implantable drug delivery devices used for anticancer therapy. ND = not disclosed.

Product Name Implant Type Material Drug Delivered Indication References

Zoladex® Sub-cutaneous PLGA Goserelin Prostate cancer [126]
Prostap® SR Sub-cutaneous PLGA Leuprolide Prostate cancer [127]
Gliadel Carmustine Primary malignant
Intra-tumoral Silicone [114,128]
Wafers® (BCNU) glioma
Oncogel® Intra-tumoral PLGA-PEG-PLGA Paclitaxel Oesophageal cancer [129]
Methacrylate
Vantas® Sub-cutaneous Histrelin Prostate Cancer [130,131]
based hydrogel
Non-muscle invasive
GemRIS® Intra-vesical ND Gemcitabine [132]
Bladder Cancer

Drug delivery to the posterior segment of the eye is difficult due the unique anatomical and
physiological barriers that the ocular environment presents [133]. Successful treatment of ocular
conditions requires that the dose of drug or therapeutic agent is delivered to the site of action and
retained for the duration that the treatment is required. This is particularly challenging in the eye
because of poor drug permeation and poor drug retention in the eye due to lacrimation, tear dilution
and tear turnover [134]. These issues are also compounded by poor patient compliance and difficult
device use associated with ocular conditions [134,135]. Implantable drug delivery devices overcome
some of these challenges to delivery by reducing the number of treatment applications required, but
also come with their own challenges including: burst release, the possibility of dose dumping, and
low bioavailability [134]. Table 3 highlights some examples of implantable ocular devices that have
been developed.
Polymers 2018, 10, 1379 16 of 24

Table 3. Examples of implantable drug delivery devices used to treat ocular diseases.

Product Name Implant Type Material Drug Delivered Indication Reference

Pilocarpine, Open angle
Ocusert® Intra-ocular PEVA [136]
Alginic acid glaucoma
Microcrystalline
Non-infectious
Retisert® Intra-ocular cellulose, PVA, Fluocinolone [137]
uveitis
Magnesium stearate
CMV retinitis in
Vitrasert® Intra-ocular PVA, PEVA Ganciclovir [138]
AIDS patients

The use of implantable drug delivery devices for pain management is promising. Chronic
pain is particularly difficult to treat and is associated with a high risk of addiction or death from
overdosing. Implantable drug delivery devices have the potential to be of use in infectious diseases,
and in particular tuberculosis (TB). The treatment for TB is long and the drugs used are associated
with side-effects. These factors result in poor patient compliance with the treatment regimen and
often leads to treatment failure and the development of resistance. In this context, an implantable
drug delivery device would be ideal to ensure patient compliance and completion of the treatment.
Poor patient compliance to antipsychotic therapy is a common occurrence and causes a high risk of
relapse, hospitalisation and other negative outcomes [139]. About 50% of patients with schizophrenia
are thought to be non-compliant with their prescribed medication [140]. Parenteral administration
of antipsychotics offers advantages such as: increased bioavailability, lower drug serum levels and
decreased variation in drug plasma levels [140]. As well as these advantages, use of a long-acting
implantable drug delivery device would ensure 100% patient compliance. An overview of some
examples of implantable drug delivery devices used for pain management, infectious diseases and
central nervous system disorders are summarised in Table 4.

Table 4. Examples of implantable drug delivery devices for pain management, infectious disease and
central nervous system disorders. ND = Not disclosed.

Therapeutic
Product Name Implant Type Material Drug Delivered Indication References
Indication
ND PU, Chronic
(Axxia Sub-cutaneous PEG/PPG/ Hydromorphine neuropathic [141]
Pharmaceuticals) PTMEG pain
Pain Interstitial
LiRIS® Intra-vesical Silicone Lidocaine cystitis/bladder [142,143]
pain syndrome
Probuphine® Sub-cutaneous PEVA Buprenorphine Opioid abuse [144]
ND ND PLGA Isoniazid TB [145]
Infectious Diseases Isoniazid,
ND ND PLGA TB [146]
Pyrazinamide
Med-Launch Sub-cutaneous PLGA Risperidone Schizophrenia [8,147]
Central Nervous
ND Sub-cutaneous PU Risperidone Schizophrenia [148]
System disorders
Risperdal consta® Intra-muscular PLGA Risperidone Schizophrenia [149]

8. Conclusions
The market for polymeric implantable drug delivery devices is one that is growing. The
advantages that this delivery route demonstrate over more conventional drug delivery methods,
such as oral tablets, make it likely that it will continue to grow and that the number of implantable
drug delivery devices on the market will increase. However, implantable drug delivery devices have a
number of disadvantages including the invasive nature of this delivery method. The advantages that
these devices can offer with respect to patient compliance, stability of drugs within these devices and
removability if adverse reactions occur, outweigh these disadvantages that exist. Current therapeutic
applications of implantable drug delivery devices are covered in this article. However, the use
Polymers 2018, 10, 1379 17 of 24

of implantable drug delivery devices has the potential to span far greater than these conditions
mentioned. One such condition where these devices could have a major impact is in the treatment
or prevention of human immunodeficiency disease (HIV). 3D printing offers an interesting prospect
as an exciting new manufacturing method, one which provides a unique opportunity to produce
complicated designs or personalised implantable devices. However, when compared to more
traditional methods of implantable device manufacture, such as hotmelt extrusion or compression
moulding, this manufacturing method comes with additional scale up and regulatory challenges. The
FDA approval of the first 3D printed tablet in 2015 makes the reality of 3D printing as a pharmaceutical
manufacturing method much more likely.

Author Contributions: This article conceptualised by S.A.S. and E.L. The article was written by S.A.S., J.D.-R. and
E.L. E.L. and R.F.D. reviewed the article.
Funding: Sarah A. Stewart is a PhD candidate funded by Department for the Economy (Northern Ireland) studentship.
Conflicts of Interest: The authors declare no conflict of interest.

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