Polycaprolactone: Synthesis, Properties, and Applications

POLYCAPROLACTONE: SYNTHESIS, PROPERTIES, AND
APPLICATIONS
1. Introduction
Polycaprolactone (PCL) is a polymer composed of hexanoate repeat units, included

in the class of aliphatic polyesters. PCL has been thoroughly investigated for its
peculiar mechanical properties, miscibility with a large range of other polymers,
and biodegradability. The physical, thermal, and mechanical properties of PCL
mainly depend upon its molecular weight and degree of crystallinity, which also
contribute to its capability to degrade—by hydrolysis of its ester linkages—under
physiological conditions. PCL is strongly hydrophobic, semicrystalline, highly sol-
uble at room temperature, and easily processable due to the low melting temper-
ature and exceptional blend compatibility, thus stimulating researchers to study
potential applications, mainly in the biomedical field (1). Indeed, owing to its na-
tive biocompatibility and biodegradability, PCL has been extensively studied for
the preparation of controlled drug delivery systems by several formulations of
polymers or copolymers. Moreover, its permeability to a wide range of drugs en-
abled uniform drug distribution in the matrix, assuring a long-term release—up to
several months—by a degradation mechanism. Owing to a markedly slow degra-
dation rate, PCL has been largely used for the preparation of long-term implants
and scaffolds able to reproduce the natural extracellular matrix, thus support-
ing the three-dimensional (3D) cell culture in tissue engineering and repair (2).
Hence, PCL has also been certified as FDA approved (Food and Drug Adminis-
tration, USA) and CE registered mark (European Community) for use in a large
number of drug-delivery and medical devices, even though surprisingly few have
been commercialized or widely translated to clinical studies.
More recently, PCL attracted interest for the design of green materi-
als/biomaterials used for various applications. The superior rheological and vis-
coelastic properties over many of its aliphatic polyester counterparts render PCL
easy to manufacture and manipulate into a large range of biodegradable devices.
Moreover, PCL mechanical properties make it suitable for medical applications
complementary to tissue engineering, such as, for example, wound dressing, con-
traceptive, and dentistry (3) but also in non medical fields such as environment,
packaging, and food (4,5). Much attention is currently put on the use of PCL in
combination with biopolymers, owing to its interesting biofriendly features. These
include tailorable degradation kinetics and mechanical properties, ease of shaping
and manufacture enabling appropriate pore sizes conducive to tissue in-growth,
and the controlled delivery of drugs contained within the matrix. In the latter case,
1
Encyclopedia of Polymer Science and Technology. Copyright c⃝ 2017 John Wiley & Sons, Inc. All rights reserved.
DOI: 10.1002/0471440264.pst658
2 POLYCAPROLACTONE: SYNTHESIS, PROPERTIES, AND APPLICATIONS
functional groups could also be added to modify polymer chains to improve hy-
drophilic, adhesive, or biocompatible properties to induce favorable cell responses.
In addition, PCL formulations have also been prepared by self-assembly to form
micro-/nanomicellar hydrogel structures after copolymerization to make them
amphiphilic, hence improving the encapsulation of bioactive molecules and drugs
(6–8).
Herein, we review the state of the art on the use of PCL as green and biomed-
ical material over the past two decades. In the first part, we focus on the main
synthesis strategies while underlining the effects of chemical synthesis onto the
main functional properties such as biodegradation. Then, we provide a compre-
hensive description of the processing techniques used to manipulate PCL in the
molten state or in solution. The article concludes with a discussion of representa-
tive platforms (ie, porous scaffold, micro- and nanocarriers, implantable systems)
applied recently as biodegradable devices for biomedical applications and green
chemistry.
2. Synthesis
The first synthesis of PCL by thermal treatment of 𝜀-caprolactone was reported

by Van Natta and co-workers (9). Since the first approaches toward the real-
ization of this biodegradable polyester, PCL is still mainly synthesized by ionic
and metal catalyzed ring-opening polymerization (ROP) of the cyclic monomer 𝜀
-caprolactone (10), even if several works have been focused on the radical ring-
opening polymerization (RROP) of 2-methylene-1,3-dioxepane (MDO) (11,12),
using different conditions, and on the condensation of 6-hydroxycaproic acid
(Fig. 1).
As concerning the polycondensation of 6-hydroxycaproic acid, this synthetic
route is only reported in a few papers (13). The most interesting approaches are
based on the enzymatic synthesis, such as those based on the use of lipase (14).
The use of Candida Antarctica Lipase B (CALB) immobilized on acrylic resin (15)
slowly gives rise to PCL with an average degree of polymerization (DPavg ) of about
63 and a polydispersity of 1.6. Interesting results for the synthesis of PCL and the
in situ production of PCL-based nanocomposites have been recently reported by
using CALB immobilized on organomodified nanoclay (16).
Another synthetic approach to PCL is the RROP of cyclic ketene acetals, pro-
posed by Bailey and colleagues in the 1980s (17). Although studies available on
this method are still limited, RROP is potentially very interesting for different
factors. First, RROP allows the random combination of ester and vinyl units for
the synthesis of several biodegradable poly(vinyl-co-ester)s (11) using radical ini-
tiators such as azo-bis-isobutyronitrile or organic peroxides. During the RROP of
cyclic ketene acetals in the presence of vinyl monomers, the reaction mechanism
and the structure of the obtained copolymer strictly depend on the ring opening of
the cyclic monomer over the 1,2-vinyl addition, that is conditioned by the compo-
sition of the monomer mixture, the temperature, the ring size of the cyclic ketene
POLYCAPROLACTONE: SYNTHESIS, PROPERTIES, AND APPLICATIONS 3
O cat lonic o
alyz rm
e e
pol d ring tal-
ym
eriz open
atio ing
n
ε‐Caprolactone
O
H2C O n
g PCL
nin
O ope
O l r ing ation
a eriz
dic
Ra olym
ion
p
sat
2‐Methylene‐
den
1,3‐dioxepane
Con
HO
OH
O
6‐Hydroxycaproic
acid
Fig. 1. Synthetic routes to PCL by ionic or metal-catalyzed ROP of 𝜀-caprolactone, by

RROP of MDO and by condensation of 6-hydroxycaproic acid.
acetal, and its substituents. For seven-member rings, such as MDO, the ring open-
ing was almost quantitative even at low temperatures (50◦ C).
Agarwal and co-workers (18) investigated the effects of the monomer ra-
tio and the temperature on the kinetic and the mechanism of the copolymer-
ization between MDO and vinylacetate, showing comparable reactivity of the
two monomers. Other vinyl monomers copolymerized with MDO for the re-
alization of functional biodegradable polyesters include styrene (19), methyl
methacrylate (20), methyl acrylate (21), glycidyl methacrylate (22,23), dimethyl
aminoethyl methacrylate, and propargyl acrylate (24). Recently, photoactivated
cobalt-mediated radical copolymerization of vinylacetate and MDO has also been
reported (25).
The detailed discussion on copolymers obtained from MDO by using differ-
ent synthetic approaches is out of the scopes of this contribution. Nevertheless, it
should be mentioned that several recent studies have been focused on reversible
addition-fragmentation chain transfer (RAFT) polymerization (also reported as
MADIX, macromolecular design via interchange of xanthates) to realize copoly-
mers of MDO and vinyl or acrylate monomers with controlled functionalities,
molecular weights, and polymer architectures (26–29). In addition, vinyl acetate
derivatives, such as vinyl bromobutanoate, have been copolymerized with MDO
using the RAFT/MADIX polymerization technique (30).
Another notable aspect of the RROP of cyclic ketene acetals, and in partic-
ular of MDO, is that the structure of PCL obtained with this method is different
with respect to that obtained by ionic or metal catalyzed ROP of 𝜀-caprolactone.
A detailed investigation on PCL obtained by RROP (31) showed 1,4- and 1,7-
H-transfer reactions leading to branched structures (Fig. 2). The branching is a
CH3
1,7‐H‐abstraction
O
O O O
O
H3C O O
H 2C O n
O
O t‐Butylperoxide
120°C
O
2‐Methylene‐
O O O
1,3‐dioxepane H 3C O
O n O O
CH3
1,4‐H‐abstraction
Fig. 2. Branched structures in PCL obtained by RROP of MDO through 1,7- and 1,4-H-
abstraction.
relevant phenomenon, because, depending on the experimental conditions, up to

20% branch density can be obtained. In some cases, the 1,4-H-abstraction reac-
tions can be avoided, bringing to PCL in which only 1,7-H-abstraction reactions
are present. The presence of these branching affects the crystallization of PCL,
bringing to a highly amorphous polymer. This property has been used to realize
blends of semicrystalline PCL obtained by ROP and amorphous PCL obtained by
RROP, and these blends have shown a drastically increased compostability with
respect to traditional PCL, even at low amounts of RROP–PCL (32).
As stated, ROP of 𝜀-caprolactone is the preferred route for the synthesis of
PCL (10). The cyclic monomer is industrially obtained by the Baeyer–Villiger
oxidation of cyclohexanone with hydrogen peroxide in the presence of differ-
ent catalysts/initiators (33,34). The main mechanisms for the ROP of lactones
(ionic and coordination–insertion), depending on the initiator used, are shown
schematically in Fig. 3. They have been well summarized by Labet and Thiele-
mans (13), that have already reported an exhaustive list of the experimental con-
ditions used for the synthesis of PCL, including solvents, concentration ratios be-
tween monomers and catalysts/initiators, temperatures, reaction times, conver-
sions, molecular weights, and polydispersity indexes of the realized polyester.
During ROP, intramolecular (backbiting) and intermolecular transesterifi-
cation side reactions must be considered, significant at the late stages of polymer-
ization, inducing in general a loss in the control of the reaction and in particular
an increased polydispersity.
As concerning ionic ROP, anionic and cationic ROP are reported. Anionic
ROP (Fig. 3a) is based on anionic species able to attack the carbonyl carbon of 𝜀-
caprolactone, inducing the ring opening and the formation of a growing alkoxide.
Intramolecular transesterification is a relevant side reaction of this mechanism.
An example of anionic ROP is found in the presence of alkali metal–based initia-
tors (35).
O –
O R O
a O – O –
R O
R
O
R
O O
+ O
b O O O
R+ R O+ O
O
O R O O M
O
c O M O O O R
M O
Fig. 3. Mechanisms of the initiation steps of (a) anionic, (b) cationic, and (c) coordination-
insertion ROP of 𝜀-caprolactone.
Cationic ROP (Fig. 3b) is based on the attack of a cation to 𝜀-caprolactone

with the formation of a positively charged species, which is then attacked by an-
other monomer that induces the ring opening through a SN2 mechanism (36). An
example of cationic ROP is found in the presence of Lewis acids (37).
The most common ROP used for the synthesis of PCL is based on the
coordination–insertion mechanism (Fig. 3c), which proceeds through the coordina-
tion and the reaction of 𝜀-caprolactone to a metal-based catalyst and the formation
of a growing species linked to the metal atom by an alkoxide bond.
An extensive use of metal complexes is reported for the synthesis of PCL
based on the coordination–insertion mechanism (38). These complexes allow
to obtain very high molecular weights (up to 800,000 g mol−1 ) and low poly-
dispersity, close to 1.1. In particular, tin(II) 2-ethylhexanoate (39) and alu-
minum(III)isopropoxide (40) are widely used catalysts.
More recently, the use of several transition metal catalysts (based on tita-
nium and zinc) and rare earth metal catalysts has seen an even growing inter-
est. Apart from the synthesis of the homopolymer PCL, research has been widely
focused on the synthesis of several classes of copolymers, to tailor material prop-
erties toward specific aims. With this objective, copolymers of PCL have been in-
vestigated for a wide range of comonomers for biomedical applications including
tissue engineering and drug delivery. In particular, these synthetic biodegradable
polymers, using the approach described in a comprehensive review (41), can be
classified in three main groups: (1) polyesters, (2) polymers containing both ester
and other heteroatom-containing linkages in the main chains, and (3) polymers
with heteroatom-containing linkages other than ester linkages in the main chains.
For instance, the synthesis of di- and tricomponent polyesters, including poly[(l-
lactide)-co-(𝜀-caprolactone)] and poly[glycolide-co-(l-lactide)-co-(𝜀-caprolactone)],
has been proposed to realize materials combining the elasticity of PCL and
tailored degradation times.
Fig. 4. Representative advanced polymeric architectures employing PCL segments. PCL

segments are represented by red polymer chains (adapted from Ref. 38).
Moreover, several research studies have been focused on PCL copolymers for
the realization of materials with advanced molecular architectures (38), such as
those presented in Fig. 4.
3. Biodegradation
One of the key factors that have contributed to the wide use of PCL in different ap-
plications is its biodegradability. PCL can be biodegraded by living organisms such
as several bacteria and fungi (42–44), thus resulting susceptible to biodegrada-
tion in different biotic environments (45). As concerning biomedical applications,
in vivo biodegradation of PCL has been widely demonstrated (46–48). Enzymatic
degradation of PCL can also occur, as it has been reported that esterase and other
kinds of lipase are able to degrade the polymer (49).
Degradation times of PCL depend on its molecular weight, crystallinity de-
gree, and morphology (50). Faster degradation was observed in the amorphous
phases (51). In particular, PCL degradation starts with water diffusion into amor-
phous regions, followed by hydrolytic scission of ester bonds (10) first in the amor-
phous phase and then in crystalline domains. The degradation is self-catalyzed by
carboxylic acids formed by hydrolysis, but, as above mentioned, it can also be cat-
alyzed by enzymes. The biodegradation of PCL proceeds through surface or bulk
degradation pathways. The difference between these two mechanisms is very rele-
vant, in particular for drug-release applications, as they strongly affect the kinetic
of the release. Nevertheless, it must be considered that often both these mecha-
nisms occur simultaneously and that the overall degradation depends on their
relative extent. Surface erosion occurs when the rate of erosion exceeds the rate
of water permeation into the bulk of the polymer (52). This mechanism is gen-
erally appreciated for drug delivery because the rate of drug release is highly
reproducible and can be tailored varying the surface area of the polymer device.
The pure surface erosion mechanism can lead to zero-order drug release kinetics.
Bulk surface erosion occurs when water molecules are able to permeate the poly-
mer matrix at a rate quicker than erosion. In this case, macromolecules in the
bulk can be hydrolyzed, inducing the formation of low molecular substances that,
diffusing into the bulk, contribute to make very complex the mechanism of poly-
mer degradation/erosion. Moreover, diffusion of water into the bulk of the polymer
does not protect embedded drugs from possible degradation. Bulk degradation
with random hydrolytic scission of the polymer chain is the prominent degrada-
tion mechanism of several polyesters, including PCL. While the low predictability
of the release kinetics and the lack of protection of drug molecules are consid-
ered disadvantages, the bulk erosion mechanism has not inhibited the wide and
successful employment of PCL for drug delivery devices.
Nevertheless, the alteration of the PCL degradation pattern has been for
years an important research field, with the objective of modulating the biodegra-
dation kinetics of the polymer. In this respect, modifications of the polymer
backbone by copolymerization with other monomers have proven to significantly
affect the degradation mechanism and kinetics of PCL for biomedical appli-
cations, in particular for pharmaceutical formulations (53). Higher degrada-
tion rates are obtained by addition of hydrophilic monomers, which also dis-
turb the crystalline aggregation of PCL blocks, thus promoting faster water
diffusion. This is the case of multiblock copolymers of PCL and poly(ethylene
oxide) (PEO), in which the biodegradation rate depends on the length of ho-
mopolymer blocks and on their relative content. For a given length of the PEO
blocks, the rate of degradation of the copolymer decreases as the PCL con-
tent increases. Moreover, longer PEO segments increase the degradation rate of
the copolymer. Nevertheless, it must be underlined that at high PEO contents
(ethyleneoxide/caprolactone ratio 3.4), copolymers containing longer PEO seg-
ments, more prone to crystallization, are characterized by lower biodegradation
rates (54).
Different is the case of well-studied PCL/poly(lactic acid) (PLA) copoly-
mers, as PLA is less hydrophilic than PEO. PLA/PCL/PLA triblock copoly-
mers show faster degradation kinetics than neat PLA and PCL. For the same
length of the central PCL block, the length increase of PLA external segments,
rendered the fastening of the in vitro degradation process less pronounced
(55). Fernandez and others (56) recently prepared poly(𝜀-caprolactone-co-L-
lactide) with 88–94% of 𝜀-caprolactone and semialternating (R → 2) distribu-
tion of sequences, and poly(𝜀-caprolactone-co-𝛿-valerolactone) copolymers with
𝜀-caprolactone molar content ranging from 76% to 85% and random (R ∼ 1)
chain microstructures. Both classes of copolymers showed faster degradation
rates than PCL homopolymer. In particular, the copolymers containing lactide
presented the fastest degradation rates, six to ten times higher than that of
PCL homopolymer. This phenomenon was attributed to the reduced ability of the
Fig. 5. SEM micrographs of PCL (a) and PCL/cellulose (b) films after soil burial degra-
dation showing the formation of irregular holes (a) and grooves (b) on the film surface.
copolymers to crystallize and to their large structural disorder. The copolymers

containing 𝛿-valerolactone also showed higher in vitro degradation rates, three to
five times higher than that of PCL.
Blending and composite technology were also used to modulate the degra-
dation properties of PCL either for biomedical or packaging applications (57).
PCL/starch blends and composites have been widely studied, and different prod-
ucts have been commercialized with tailored properties, included biodegradabil-
ity (58–60). The evaluation of enzymatic degradability showed that lipase degra-
dation of PCL and 𝛼-amylase degradation of starch increased with the starch
content. This can be explained by the increased available interfacial area of
PCL after blending with starch, which resulted in increasing its susceptibility to
hydrolysis.
Also PCL/cellulose composites have been realized and characterized for dif-
ferent applications (61). For this class of materials, the effect of the crystallinity
and morphology of the cellulose filler on the biodegradation properties of PCL
has been investigated (62). Soil burial degradation tests of PCL/cellulose revealed
that composites containing amorphous cellulose undergo a faster degradation
with respect to composites containing short- and medium-length cellulose fibers.
This phenomenon was explained considering the higher water absorption capac-
ity of PCL composites containing larger amounts of amorphous cellulose, as due
to the evidence that the amorphous fraction of cellulose is more accessible to wa-
ter molecules with respect to the cellulose crystalline domains (63). At 30 wt%
of amorphous cellulose loading, soil burial degradation induced about 25 wt% of
weight loss in 74 days, compared to the about 5 wt% of weight loss for neat PCL.
Moreover, the biodegradation kinetics was slowed down for compatibilized com-
posites since, in this case, compatibilized composites showed a decreased tendency
to water absorption with respect to uncompatibilized ones. As reported in Fig. 5a,
the biodegradation of PCL/cellulose films occurred through the formation of irreg-
ular holes. The PCL/cellulose weight ratio resulted almost unchanged at the end
of the experiments, indicating that the biodegradation of the composites involved
both cellulose and PCL phases. Another interesting aspect to be underlined is the
formation of grooves on the surface of the films, shown in Fig. 5b, and attributed
in the literature to the degradation of the amorphous fraction of PCL (64), con-
firming that the degradation of the polyester starts from the noncrystalline PCL
phase.
4. Polymer Processing
4.1. PCL Melting Processes. Extrusion is the most used technology

in plastics industry since it is a continuous, very flexible process and allows
high throughput. This technology has also been applied to the processing of PCL
(65–67). The extrusion process aims at melting the polymer to give a proper shape
(film, plate, tube, and so on) and/or mixing with additives to obtain compounds or
blends with improved mechanical or functional properties (68). It is usually based
on one or two rotating screws that convey the polymer along a plasticating barrel
through a die, specifically designed to take into account the polymer viscoelastic-
ity. The die is responsible for the polymer forming to get the desired shape, which
can be a finished or semifinished product. The extruder can be used alone or as a
part of a more complex polymer treating plant, such as in the injection molding
or foaming processes, or as a part of a multiextruder line.
One of the major extruder design parameters is the number of screws. In
general, single-screw extruders are preferred to twin-screw types for their cost
(roughly half the price of a twin-screw extruder) and their easier understand-
ing and maintenance. Single-screw extruders are also preferred in the production
of biodegradable polymers since they are characterized by a lower mixing inten-
sity, which translates in lower shear stresses applied to the polymer and hence
in lower chemical degradation (69). Twin-screw extruders are preferred for their
higher performances such as greater and more steady feeding, higher through-
put, higher mixing efficiency (but with higher stress transmission to the melted
compound), and better dispersion of additives, better temperature control, and
homogenization (70). The twin-screw extruder is also frequently used for foaming
since it is able to quickly and more efficiently disperse the blowing agent, respon-
sible for the formation of the porosity (71,72), and it can easily guarantee a strong
and stable dynamic sealing before gas injection points.
The extruder has the capability to sequentially perform subprocesses along
its length. These can be specifically performed by properly designing the screw
profile, in particular recurring to segmented designs. Segmented screws are highly
desirable because elements can be strung onto screw shafts to optimize subpro-
cesses and can be changed accordingly to the specific processing needs and poly-
mers, without the need to replace the entire screw. Both single- and twin-screw
extruders can be used to process PCL, and their choice have to be related to the
specific performance needs of the final product.
The main components of an extrusion line can be schematized in three con-
ceptual zones: polymer feeding, plasticating, and feeding through the shaping die.
Usually more complex designs are used to correctly perform the process, in par-
ticular if blends, compounds, or foams have to be produced. The extruder often
presents the following zones:
1. materials feeding,
2. melting and compounding of additives,
3. gas injection and solubilization (in case foams have to be produced),

4. melt homogenization and cooling,
5. metering through the die, and
6. die and postdie forming.
In the case of PCL extrusion, the melting, pumping, and forming subpro-
cesses have to be performed in a process window that avoids polymer or additives
degradation. This particular care has effects on a lot of parameters, such as the
choice of the screws types and segmenting, formulation modifications, and operat-
ing conditions. To reduce the mechanical stresses on the polymer melt but at the
same time to guarantee a correct dispersion of all the components, static mixers
or open meshing elements can be used. The latter are preferred since the pres-
sure rise is distributed over a larger length of barrel, and the heat transfer and
thermal homogenization are obtained with lower energy consumption.
A homogeneous temperature of the melt at the die exit is very important
since the viscoelastic properties of the extrudate are extremely sensitive to it. The
production of finished or semifinished products needs a precise control of the exit
temperature, which usually has to be lowered to increase the melt strength of the
polymer. This task is particularly difficult to obtain if a single extruder is used
since it conflicts with the plasticating function of the extruder and is typically
addressed by using a long barrel. If a fine control of the processing conditions
is needed and the higher cost can be managed, a second extruder operating in
tandem with the plasticating one is the best solution. This solution is particularly
effective since it allows to decouple the plasticating/mixing tasks from the shaping
ones or further processing (eg, foaming), operated by the second extruder that
takes care of the melt cooling to a temperature range where good quality products
can be obtained.
If only melting and moderate mixing are needed, a single-screw extruder
would be adequate. However, in most cases different components have to be in-
timately dispersed in the polymer and their agglomeration has to be carefully
avoided. This is generally better addressed by using a twin-screw extruder, which
may deagglomerate and disperse the nucleating agents, colorants, as well as fillers
in a controlled way that ensures homogeneous properties throughout the extru-
date. Furthermore, if blending of two polymers is part of the compounding process,
the twin-screw design is quite mandatory.
4.1.1. PCL Blends. PCL has been widely blended with other polymers to
increase its thermal, viscoelastic, or mechanical properties. Moreover, PCL has
been used as a minor phase in binary or ternary systems to increase their func-
tional properties. Among all biodegradable blends, PCL/PLA has been one of the
most investigated. The main reason for such system is the possibility of an in-
crease in the mechanical and thermal properties of PCL, which are weak for any
industrial need that requires just a moderate tolerance to temperatures above
room temperature. Blends can be obtained either by physical blending or by re-
active extrusion. Since PCL and PLA are not miscible, the physical blend still
presents two distinct glass transition temperatures (73,74). To overcome such a
problem, they have to be compatibilized to take advantage of PLA peculiarities
(75,76). Reactive compatibilization has been investigated by Wang and co-workers
(77) that prepared PLA/PCL blends by means of three coupling agents, aimed at
exploiting a transesterification reaction to increase their compatibility. They suc-
ceeded in producing compatibilized blends, with higher elastic modulus but lower
strength with respect to physical blends of the same composition. The main draw-
back was the increased degradation rate of the reactively compatibilized blends
that was much higher than that of pure PLA and PCL. On the contrary, the degra-
dation rate of physical blends is between those of pure PLA and PCL.
Blends of PCL and starch and its derivatives have been investigated by
Koenig and Huang (78). They found that some degree of cross-linking was needed
to improve the thermal properties of the blends. In not compatibilized systems, two
phases were clearly detectable with both optical microscopy and thermal analy-
sis. The phase morphology was typical of particle-reinforced systems, where starch
particles were dispersed in the PCL matrix, and the advantages were an increase
of the elastic modulus (+ 50% with respect to PCL) at the expenses of a reduc-
tion of the tensile strength (- 15% with respect to the neat polymer). A reactively
extruded starch–PCL nanocomposite blend was prepared by Kalambur and Rizvi
(79), who found that the viscosities of nanocomposite blends were significantly
lower than that of 100% PCL and nonreactive starch–PCL composites synthesized
from simple extrusion mixing. Thermoplasticized starch (TPS) and PCL blends
were prepared to overcome some weakness of pure TPS, such as viscosity and
thermal degradability (80–83). The presence of PCL can affect significantly the
rheological behavior of the blends, as well as it can improve the thermal stability
of the blend (Fig. 6).
Even at low PCL content, for example, 10 wt%, different mechanical (re-
silience) as well as functional (moisture sensitivity and shrinkage) properties are
improved but they are significantly conditioned by the phase morphology (80).
PEO/PCL blends were prepared for oral drug delivery applications. In this system,
PCL was used to reduce the drug release rate profile (69). The authors also found
that the performance of the blend was dependent on the processing conditions, and
in particular on the shear stresses and temperatures applied during the mixing
process. In fact, higher screw speeds were observed to result in slightly lower ma-
trix melt viscosity when compared with matrices compounded using lower screw
speeds. Other authors confirmed the immiscibility of PCL/PEO blends and found
that the crystallization process of PCL was not affected by the PEO amount (84).
Blends of PCL and proteins have also been investigated. Proteins extracted
from plants attract special attention in the production of biodegradable polymers.
Proteins such as zein (corn), gluten (wheat), soy protein isolate (SPI), and peanut
protein (85) have been used. SPI has been widely investigated (86–89). Owing to
the very difference affinity of proteins and PCL, a compatibilizer must be used,
such as polyvinyllactam, methylene diphenyl diisocyanate, or modified cornstarch.
The use of the compatibilizer leads to the increase of the elastic modulus and
strength but lowers the plasticity (lower strain to failure). An effect of the addi-
tion of PCL is the reduction of water absorption and the increase of stability under
ambient conditions relative to the plastics made from soy protein alone. John and
colleagues (90) modified PCL to incorporate a functional group that could inter-
act with the functional groups on the gluten protein. Their results showed that
a small amount of anhydride-modified PCL in the blend improved the physical
properties of these blends over those of simple mixtures of wheat gluten and PCL.
12
Fig. 6. (a) Storage modulus versus frequency plot for PCL/TPS blends at 170◦ C (PCL content decreases going from the lower curve to the
upper one) and (b) TGA curves of PCL/TPS blends (PCL content decreases going from upper to lower curve) (Reprinted with permission
from Ref. 83. Copyright 2004 Wiley).
The presence of different phases and the use of high amount of proteins can result
in a narrowed window of processability and decreased elongational strength.
Ternary systems, such as PCL–starch–low density polyethylene (LDPE),
have also been prepared by Matzinos and others (91). The ternary blend was pre-
pared by means of the extrusion process, which induced the thermoplasticization
of the starch, and formed in film and molded parts. The resulting morphology was
with separate phases since the authors did not use any compatibilizer. The me-
chanical performance was found to depend not only on the composition but also
on the generated morphology. In films, the fine dispersion of PCL in the polyethy-
lene/starch matrix resulted in increased mechanical properties, whereas in injec-
tion moulded specimens there was a decrease in properties due to phase coales-
cence. The ternary blend based on PLA/PCL/TPS was prepared by Sarazin and
co-workers (92), who produced the blends by using a one-step extrusion process
with the aim of exploiting PCL to increase the plasticity of PLA. The morphol-
ogy and quantitative image analysis of the blends exhibited a three-phase mor-
phology, with a fine dispersion of PCL “particles.” The thermomechanical analysis
clearly showed that the temperature of the tan 𝛿 peak of PLA is independent of
TPS blend composition and that the addition of PCL in the ternary blend has
little influence on the blend thermal transitions. The coupling of PLA with PCL
and starch resulted in an increase in ductility (elongation at break up to 55%
from 5% for the pure PLA) and of notched Izod impact energy, clearly indicat-
ing a synergistic effect that exceeds the results obtained for any of the binary
pairs.
To improve the interface interactions between PCL and other polymers, dif-
ferent routes have been investigated such as polymer/polymer inclusion com-
pounds, such in the case of PLA/PCL blends (93), or grafted copolymers (94,95).
The managing of the compatibility between the two or more phases in a blend can
result in the tailoring of additional characteristics such as rate of biodegradation
and mass transport of low molecular weight species (water vapor, CO2 ) other than
thermal transitions and mechanical behavior. PCL grafted onto starch through in-
troduction of urethane linkages was very effective in increasing the mechanical
properties with respect to not compatibilized blends (94). Furthermore, the blend
did not show the typical two melting temperatures (Tm ) of phase-separated sys-
tems because a single Tm after PCL was compatibilized. Also the crystallization
temperature can be influenced and its depression can be controlled through the
amount of compatibilizer added to the blend.
4.2. Processing via PCL Solution.
4.2.1. PCL-Based Porous Materials. In the past years, several tech-
niques have been used to manipulate PCL in the form of porous matrices (96). Con-
ventional fabrication techniques such as salt leaching (97), gas foaming (98,99),
phase separation (100), and freeze-drying (101,102) have been mostly used, de-
spite they do not offer a precise control of internal scaffold architecture and their
properties (ie, mechanical ones) for the fabrication of complex architectures. The
gas foaming is a processing technique that allows the fabrication of biodegrad-
able foams with porous architecture suitable for green applications in different
fields (ie, biomedical, environment, energy). The main advantage of this tech-
nique is related to unique chance of forming the porous network avoiding the
use of organic solvents that may be harmful in biological or biosafe environment.
During the gas-foaming process, the polymer is saturated with a gas or su-
percritical fluid—usually CO2 , N2 , or their mixture—under constant process-
ing conditions (ie, temperature, pressure). When the solubilization of the blow-
ing agent into the polymer is completed, the polymer/blowing agent solution
is brought to the supersaturated state either by increasing temperature (ie,
temperature-induced phase separation) or by reducing pressure (ie, pressure-
induced phase separation), with the effect of inducing the nucleation and growth
of gas bubbles into the polymeric matrix. These mechanisms play a key role
in controlling—by an accurate setting of processing parameters—the final foam
morphology (103). For instance, Xu and colleagues prepared biodegradable PCL
foams in the presence of supercritical CO2 gas (104). They reported that lower
depressurization rate and saturation temperature led to increased foam bulk
density.
Alternatively, PCL porous matrices have largely been fabricated via thermal
induced phase separation (TIPS), a complex process depending on the thermody-
namics and the kinetics of the polymeric solution during cooling (105). The basic
idea provides the cooling of a polymer solution to induce a phase separation in two
phases, respectively, one polymer-rich phase and one polymer lean phase. Later,
the removal of the solvent within the polymer lean phase by solvent evapora-
tion, sublimation, or solvent/not solvent exchange allows reaching an open pore
network whereas the polymer that composes the polymer-rich phase solidifies in
the final structure. Typically, a liquid–liquid phase separation occurs when the
imposed temperature is higher than the solvent crystallization one or freezing
point whereas a solid–liquid phase separation takes place when the solvent crys-
tallization temperature overcomes the cooling one. Pore characteristics (ie, micro-
tubules diameter, shape, and orientation) and structural defects may be controlled
by an accurate definition of thermodynamic parameters and mold manufacturing
(106). In the case of PCL matrices, several studies investigated the formation of
anisotropic regions due to the application of local "not intentional" temperature
gradients, which promote the growth of microsized channels—from the surface
to the inner regions—orthogonally oriented to the solidification front. This pecu-
liar architecture can be strictly controlled by the design of custom-made molds
with insulated walls able to minimize the formation of transversal gradients and
promoting a preferential heat conduction in the longitudinal direction to obtain
oriented microtubular porosity able to confer peculiar anisotropic properties (ie,
mechanical response) to the polymeric structure (100,107).
Salt leaching is based on the addition of porogen or salt crystals (eg, sodium
chloride) to a polymer solution arranged into a stable mold. This slurry (ie, poly-
mer plus porogen) is subsequently hardened by solvent removal after phase in-
version, evaporation, or separation, and only then salt is removed via dissolution
in water or alcohol thus forming a porous structure once all the salt leaches out
(108). Pore size and pore size distribution can be controlled by the size and size
distribution of the porogen used, whereas the porosity can be controlled by vary-
ing the amount of the salt particles (109). These parameters have relevant effects
on the mechanical response, consistently with changes in morphological features
(97). However, pore shape and interconnections are generally not controllable so
that particle leaching is generally combined with other scaffold fabrication tech-
niques, to create porous matrices fully percolative to fluids and small molecules.
Besides, similar drawbacks have also been recognized in other processing tech-
niques. For instance, porous PCL matrices fabricated via gas foaming generally
show a remarkable lack in pore interconnection, strictly depending upon the gas
expansion mechanism during foam formation and the inherent high melt strength
of PCL (110). In the case of PCL matrices obtained by TIPS, pore sizes are gen-
erally smaller than 100 𝜇m and are usually unsuitable to accommodate different
cells which have to stretch and adequately grow, impairing the cell proliferation
within the scaffold (111). Hence, other technological approaches (ie, rapid prototy-
ing, electrofluidodynamics) have been more recently implemented to design micro-
and nanostructured platforms with fully percolative structure by using biodegrad-
able polyesters such as PCL in solution, to overcome the main limitations of con-
ventional techniques. Rapid prototyping techniques supported by computer-aided
design (CAD) modeling have largely demonstrated to be feasible and consistent for
a finest control of the PCL scaffold architecture at both micro- and macrolevels,
but still present some relevant limitations in terms of resolution (112). Among
them, stereolithography allows photopolymerizing a liquid photo-cross-linkable
resin, such as PCL monomers in a chemically modified solution, into designed
3D structures with the highest accuracy and precision by successive deposition of
thin layers, photoirradiated by ultraviolet or visible light according to a sliced CAD
model (113). In this case, resolution of each layer is dependent on the resolution of
the elevator layer and the spot size of the laser. However, owing to the application
of an additional curing step to improve the model’s property, the final resolution
may be compromised by the shrinkage that typically occurs in this postprocessing
step (114). Alternative approaches based on the physical interaction of PCL solu-
tion with electrostatic forces (ie, electrospinning) allows prefabricating controlled
textured matrices with controlled strut sizes; however, several limitations arise for
pore sizes over the micrometer scale. Electrospinning is based on electrohydrody-
namic principles relying on an electrified viscous fluid jet being drawn through
the air toward a collector at a different electric potential (115). PCL fibers fabri-
cated via electrospinning generally present average diameters typically ranging
from 0.5 to 2 𝜇m. However, the chaotic nature of fiber deposition commonly re-
sults in tightly packed nonwoven meshes with pore sizes too small to assure an
efficient penetration of micrometric or submicrometric objects (ie, cells and molec-
ular complexes). To increase the percolation or invasiveness index of these struc-
tures, PCL may be processed in the form of melt solution that differently interacts
with electrostatic forces so producing much larger sized filaments up to 250 𝜇m
in size (116,117). More recently, PCL scaffolds by covalent attachment of a hydro-
gel component to modified methacrylated PCL segments were fabricated through
electrofluidodynamic writing processes combining unique benefits of 3D printing
technique, electrospinning, and direct writing mode (118).
4.2.2. PCL-Based Micro- and Nanoparticles. Various preparation
methods have been used in the past years for the fabrication of PCL microspheres
and the encapsulation of different drugs (Fig. 7). They include phase separation
(119), emulsion evaporation (120), solvent extraction (121), spray drying (122),
and melt encapsulation (123). In all cases, it is possible to obtain spherical mi-
crospheres with average sizes ranging from 50 𝜇m to 2 mm. Drugs or bioactive
molecules can be entrapped or encapsulated with different efficiency as a func-
tion of the used processing method. The drug may be released by matrix erosion
Fig. 7. Schematic of the main processing techniques used to fabricate PCL micro- and
nanoparticles for drug delivery applications.
and/or by diffusion trough the matrix or the shell forming a microsphere reservoir
(124). Their large surface-to-volume ratio and rigidity in shape allows controlling
drug release kinetics as a function of the peculiar properties of the polymeric ma-
trix. More in general, PCL microspheres with modulated release kinetics can be
obtained either by selection of appropriate preparation method, processing con-
dition, and/or change in polymer composition leading to a altered degradation
behavior. As a consequence, PCL microspheres have been considered for several
applications, other than in controlled drug delivery such as for drug targeting
upon derivatization or surface modification.
As first attempt, PCL microparticles have been prepared by a polymerization
of colloidal monomers dispersed in a liquid with opposite solubility (125). More
commonly, microparticles can be processed from dispersed droplets of monomeric
solutions by various methods including emulsion, suspension, and dispersion tech-
niques (126). The water (W)/oil (O) solvent evaporation method is the simplest
solution, but it is suitable for lipophilic drugs only; whereas W/O/W is useful in
encapsulating both oil and water soluble drugs (127). Alternatively, oil in oil (O/O)
and water in oil in oil (W/O/O) methods have been largely used for the encapsu-
lation of any water-soluble drug—either alone or in combination with lipophilic
drugs (128,129). By these techniques, it is possible to fabricate uniform spheres
from the macro to submicrometric scale (0.1–100 𝜇m). In the case of micromet-
ric sizes, spherical droplets can be formed by oil-soluble organic solution of PCL
dispersed in aqueous media—oil in water (O/W)—or by water-soluble monomers

dissolved in water dispersed in an organic medium—water in oil (W/O) (130). To
reduce particle sizes down to 1 𝜇m or below, polymer beads can be prepared by
dispersion polymerization into a range of 0.5–10 𝜇m, or by suspension polymeriza-
tion down to 50–500 nm, a size only detectable via visible light diffraction (131). In
these cases, reagents including monomers, initiators, and stabilizers are dissolved
in an organic medium and, since the initiator is soluble inside the monomer poly-
merization takes place inside the monomer droplet. Polymer beads, insoluble in
the organic solvent, begin to precipitate, and the stabilizer prevents bead floccula-
tion. Size and particle quantity have to be determined as a function of the relative
phase ratios and the speed of mechanical stirring (132). To improve the encapsu-
lation of bioactive molecules, a double emulsion strategy can be adopted to pre-
liminarily dissolve biomolecules into water prior to disperse them into an organic
solvent (usually dichloromethane, DCM, for PCL). Poly(vinyl alcohol) or other sur-
factants may be used to stabilize this second emulsion. In this case, microspheres
are formed as DCM evaporates and the polymer hardens, thus trapping the en-
capsulated drug (133).
All the methods previously described generally show the main disadvantage
to present residual traces of organic solvents in the final product (134). To avoid
the use of organic solvent, alternative strategies including hot melt technique and
spray drying have been adapted, case by case, to the use of thermostable drugs.
Spray drying techniques have been commonly used for producing microspheres
from linear polymers (135). In place of spray drying, freeze-drying is proved to be
more advantageous in terms of decreased particle size and increased burst release
(136).
Only recently, novel processes based on supercritical fluids such as rapid ex-
pansion, antisolvent precipitation, and solvent-enhanced dispersion are emerging
as innovative approaches to encapsulate a wide range of drugs, minimizing any
processing traces in the final formulation for the fabrication of a fully recycling
product (137).
5. Applications
5.1. Scaffolds for Tissue Engineering. Tissue engineering strat-

egy is based on the design of porous scaffolds with peculiar biodegradabil-
ity/bioresorbability of pores, to be used as 3D template for supporting cell attach-
ment and subsequent tissue formation, both in vitro and in vivo (138). 3D scaffolds
have to present suitable features for the creation of a cell friendly microenviron-
ment able to exert mechanical support, physical and biochemical stimuli for opti-
mal cell growth and function (112). For this purpose, it is mandatory an accurate
selection of constituent polymers in terms of degradation, mechanical properties,
workability by commonly used scaffold fabrication methodologies, and intrinsic
biocompatibility with cells under different culture conditions (139). For instance, a
bioinspired scaffold has to degrade up to in vivo resorb at a predefined rate so that
the 3D space occupied by the initial scaffold can progressively be replaced by the
regenerated host tissue, minimizing the inflammatory response of the substrate
(46). In this context, some aliphatic polyesters such PCL are very attractive in
tissue engineering because of their good biocompatibility and processability. In

particular, PCL homopolymer degrades extremely slowly by hydrolysis, showing
low values of water absorption and weight loss after 110 weeks in an aqueous
medium simulating body fluids (140). This behavior endows the PCL matrix with
sufficient mechanical properties to sustain reduced loads such as the hydrostatic
pressure of biological fluids inside the structure, offering a valid support function
until its complete degradation, when tissue will be totally formed (141). Moreover,
the use of a long-term degradable material such as PCL avoids stress-shielding
phenomena associated with the use of rigid implants. Indeed, the progressive
degradation of the implant may trigger a gradual stimulation of healing mech-
anisms —that is, remodeling in the case of bone—by a gradual transfer of physi-
ological loads, thus minimizing stress-shielding atrophy (142).
Besides, it is mandatory to impart peculiar functionalities able to imitate, or
at least, to regenerate the native physiochemical environment of tissues. This is
possible by imparting specific morphological and biochemical cues to PCL mate-
rials by providing an accurate manipulation of pore architecture at the micro and
nanoscale, and/or chemical modifications to incorporate bioactive phases (ie, bio-
ceramic) or molecular signals (141–147). In the past years, several studies have
been focused on the optimization of topological features such as full pore inter-
connectivity, tailored pore size, and shape that can actively support cell functions
by regulating the interaction between the cells and the diffusion of nutrients and
metabolic wastes across the whole 3D construct (148). It is well known that an
optimum pore size range may be selected as a function of cells or tissues to be
regenerated such as 5–15 𝜇m for fibroblast in-growth, 20–125 𝜇m for skin re-
generation, 100–300 𝜇m for bladder smooth muscle cell adhesion- and in-growth,
100–400 𝜇m for bone regeneration (149).
Hence, processing techniques have to be adequately selected to confer tun-
able porosity as well as mechanical properties able to carry out the most appropri-
ate biological response to PCL scaffold (Fig. 8). For instance, temperature-driven
processing routes, such as TIPS and melt co-continuous polymer blending, may
be adopted, alone or in combination with conventional techniques (ie, particulate
leaching) to fabricate multiscale porous scaffolds with peculiar structure/property
combinations. This mainly depends upon the peculiar chemical/physical proper-
ties of PCL—that is, low melting point, solubility in several organic solvents—
which allows for their easy processability under controlled thermal conditions.
For instance, in the case of PCL scaffolds fabricated by TIPS, a judicious set-
ting of solvents, cooling modalities (ie, temperature and cooling rate) enables guid-
ing the thermodynamic phenomena associated with the formation of dispersed
phases and thus giving the chance to obtain either random or oriented pore archi-
tectures (100) to mimic the anisotropic structure of natural tissues. Alternatively,
a temperature-controlled extrusion of binary blends including polymers with a
similar melting point (ie, PCL and PEO) may allow forming co-continuous 3D
microstructures as a consequence of the interpenetration of two different melt
phases able to reproduce fully interconnected anisotropic pore networks with im-
provements in the mechanical properties and fluid permeability with respect to
conventional scaffolds processed by polymer solutions (ie, salt leaching) (150). This
result is really promising to realize structurally organized platforms able to guide
19
Fig. 8. Summary of porous scaffolds made of PCL fabricated by different processing technologies from PCL solution.
the regeneration process of hierarchically organized tissues (ie, tendons, muscles,

ligaments, and nerves).
5.2. Biodegradable Carriers for Drug Delivery. Biodegradable poly-
mers currently represent one of the most interesting opportunity to design drug
delivery systems due to their relevant advantages, such as the easy removal of
polymer metabolites out of the body by innate metabolic processes, and the unique
chance to process them in the form of micro- and nanoparticulate systems to finely
control site-specific and targeted drug delivery. To date, drug administration via
degradable drug delivery systems is advantageous, giving the opportunity to de-
sign polymer microcarriers easy to be ingested or injected. For instance, they can
be tailored for organ-targeted release, by improving the biological activity, con-
trolling the drug release rate, and decreasing the administration frequency. This
is possible because the polymer matrix can biodegrade within a suitable period,
which is compatible with the drug release rate, so properly dosing active princi-
ples in the site of interest, improving the therapeutic efficiency and efficacy, but
minimizing any side effect during pharmacological treatments.
Hence, an extensive research has been carried out to explore the suitability
of biodegradable polymers not only to develop bioresorbable devices (ie, surgical
sutures) but also drug delivery systems. Among the different classes of biodegrad-
able polymers, PCL has been extensively studied in several formulations not only
for their recognized biocompatibility and biodegradable nature but mainly for its
large variability of degradation properties, which allows fruitfully using it for dif-
ferent pharmaceutical dosage forms (151). Its compatibility with a wide range
of drugs enables uniform drug distribution in the matrix, whereas its long-term
degradation facilitates drug release up to several months (152). The advantages of
PCL include its high permeability to small drug molecules, and its negligible ten-
dency to generate an acidic environment during degradation as compared to other
polyesters such as PLA and polyglycolic acid (PGAs). The degradation of PCL ho-
mopolymer is very slow compared to other polyesters, making it more suitable
for long-term delivery systems extending to a period of more than 1 year, despite
it can be increased/decreased by proper physical or chemical modifications (153).
Meanwhile, the high permeability to many drugs supports its ability to be fully
excreted from the body once bioresorbed (64). Drug release rates from PCL sub-
strates may depend upon a large pattern of parameters as function of the specific
formulation and preparation methods, such as PCL content, size, and percentage
of relative drug fractions used. Owing to the high workability, PCL may be easily
blended with other polymers to improve stress, crack resistance, dyeability, and to
better control drug release rates. However, blending strategies generally lead to
altered physical properties and biodegradation with relevant effects on mechani-
cal properties, so that this approach is generally preferred for the preparation of
platforms for tissue engineering, such as porous scaffolds, fibers, or films. In the
past years, PCL has been successfully combined with natural polymers, such as
starch, gelatin, collagen, or chitosan (154,155), as well as synthetic ones including
polyethylene glycol, polyurethane, and polyvinyl alcohol (156), to satisfy the main
requirements in terms of biophysical/chemical properties for drug-dispensing for-
mulations currently used in drug delivery.
Several studied have underlined some relevant constrains about the release
mechanisms of therapeutic compounds, which may be significantly hindered by
the poor water solubility of PCL. However, recent advances in drug formulations
based on the use on innovative colloidal vectors currently concur to improve the
drug delivery system performance, by providing a more efficient dispersion of
drugs in PCL matrices by the use of solubilizing agents (7). For example, the for-
mation of block copolymer micelles—a hydrophobic core sterically stabilized by
a hydrophilic corona—may allow for the increase of the solubility of hydrophobic
molecules by the peculiar polar interaction with local groups. In this case, chem-
ical, physical, or electrostatic interactions allow variously entrapping drugs as a
function of the physicochemical properties of macromolecules in the inner core,
thus working as reservoir systems. Within the past decade, similar approaches
have been used especially to develop controlled delivery systems for peptides and
proteins (157).
5.3. Other Medical Devices. PCL is also suitable for the fabrication of
innovative devices that are only indirectly interfaced with natural tissues, thus
requiring an intermediate level of biocompatibility.
For instance, several studies have been performed in the past 40 years to
identify the best material to be used for suturation. To date, sutures made from
aliphatic polyesters including PGA (DexonTM ), polylactic-polyglycolic acid (PLGA
10/90 - Vicryl R⃝ ), and polydioxanone (PDS) have been broadly commercialized with
different benefits as consequence of their specific biocompatible features (158). In-
deed, the main problem of suture materials concerns their inflammatory response.
It has been proved that DexonTM and Vicryl R⃝ are more invasive on the activity
of different kinds of cells with respect to PDS. Only recently, PCL has been in-
vestigated for the fabrication of suture filaments. Despite their limited applica-
bility due to their degradation in vitro via the bioerosion mechanism, different
copolymers have been investigated—that is, block copolymers of PCL with glycol-
ide commercialized as Monacryl R⃝ —to obtain monofilament sutures with reduced
stiffness compared with pure polyglycolide, commercialized by Ethicon, Inc. (159).
PCL is also one of most used resorbable polymers for wound-healing applica-
tions. In most cases, PCL is fabricated in the form of microcarriers for in vitro and
in vivo subdermal delivery of bioactive drugs (ie, L-methadone) or ultrathin film
(160) for the release of chemical antiseptic chlorohexidine by dressing cutaneous
wounds (161).
In the past two decades, relevant studies have been developed to design
biodegradable matrix implants for controlled release of contraceptives to circum-
vent the need for device retrieval surgery. PCL is a highly desirable candidate
for this role owing to its slow degradation, biocompatibility, and FDA approval.
Dhanaraju and co-workers have prepared and characterized PCL microspheres
as injectable systems for a controlled delivery of contraceptive steroids, directly
into the implant site (162). Sun and others have developed a 2-year contraceptive
device comprising PCL/Pluronic F68 compounds filled with levonorgestral pow-
der, which was approved by the FDA to conduct phase II human clinical trials in
China. Preclinical studies using rats and dogs demonstrated good release kinetics
of levonorgestral from this device, with no adverse effects. After implant retrieval
after 2 years, the implant was physically stable with an associated drop in the
molecular weight of the polymer from 66,000 to 15,000 Da (163).
Other studies suggested the use of PCL for orthopedic applications. They
mainly involve the design of composite fixation systems by reinforcing PCL with
Fig. 9. Zein–PCL package containing solid carrots (a) before high pressure treatment
and (b) after high pressure pasteurization at 700 MPa (Reprinted with permission from
Ref. 172. Copyright 2011 Elsevier).
glass fibers. The main advantage of the use of PCL is related to the lower stress
shielding with respect to metals (ie, stainless steel), traditionally used for pros-
thetic devices (142). However, mechanical strength of PCL may be not sufficient
for load-bearing applications and their use is mainly oriented to design resorbable
composite implants for craniofacial repairing where more resilient materials are
required (164). Furthermore, PCL has been reinforced with several different fibers
including knitted polymer mesh (165) or inorganic glass fibers (166,167).
5.4. Biodegradable Films for Packaging. Packaging applications are
one of the most intensely studied applications for PCL-based materials with com-
parable functionalities to those of traditional oil-based plastic packaging (168).
Despite current higher costs compared with the traditional plastic counterparts
(169), many have found increasing commercial applications in packaging (170), in
particular in the food industry (171).
PCL has preferably been used in films in blend form or coupled with other
biodegradable polymeric films through compatibilizing layers due to the low elas-
tic modulus and very fast (for packaging use) degradation (172). For example, the
use of PCL and thermoplasticized zein (TPZ) blends has proved to have excel-
lent adhesive capability in laminated PCL and TPZ-packaging structures (173)
as shown in Fig. 9. These laminated structures were found to be suitable for high
pressure pasteurization treatments (174) thanks to the combination of specific
performances allowed by each layer of the film. Tests performed on multilayer
structures confirmed the possibility to industrially use such packaging structure.
A sterilizing treatment, obtained by means of a high pressure apparatus up to 700
MPa, did not promote any detectable change of oxygen and water vapor barrier
properties of film. In Fig. 9, the appearance of pouches made of zein–PCL multi-
layer structures containing food before and after a high pressure pasteurization
are reported and no visible degradation of the film can be observed.
Other examples of PCL-based films for food packaging are reported by
Swapna Joseph and colleagues (175). The authors prepared chitosan and PCL
solution–casted blends in various proportions (chitosan–PCL ratio 90:10, 80:20,
and 70:30). The films were casted and dried at 55◦ C. The presence of PCL in
chitosan resulted in an increase in elongation by 20.56% as compared to the pure

chitosan film. PCL and chitosan showed to be miscible, and a co-continuous phase
was detected in the 80:20 chitosan/PCL blend.
Plackett and co-workers (176) have studied copolymer films based on
PLA/PCL for their suitability as materials for cheese packaging. The authors also
prepared some nanocomposite formulations to enhance the barrier properties of
the film and/or used cyclodextrin complexes designed to provide slow release of
encapsulated antimicrobials for the control of mold growth on packaged cheeses.
The systems exhibited complete biodegradation under controlled composting con-
ditions even if some issues were experienced due to the characteristic biodegrad-
ability of the film. In fact, high moisture absorption and, consequently, a decrease
in polymer molecular weight with time were detected at 25◦ C. The authors guess
was that improved performances could be exhibited at normal cheese storage tem-
peratures (∼4◦ C). In regard to the use of nanoclay, the authors verified an en-
hanced thermal stability of the polymer but were not able to get a significant
reduction of oxygen and water vapor permeability. Such result was related to the
possible poor dispersion of the nanoclays in the chosen polymer matrices.
On the other side, blending has proved to be an effective approach to improve
the mechanical response of the film as a result of the use of PLA in the blend. The
compatibility of antimicrobials, such as for the cyclodextrin-encapsulated type (al-
lyl isothiocyanate), with PLA/PCL copolymer films was demonstrated and proved
to be a viable solution to control the development of fungi on packaged cheeses
(176), without incurring in substance migration issues since those species are not
contaminant for food.
The development of an active packaging based on biodegradable matrices
is a promising route to increase the use of biodegradable polymers in industrial
packaging. Some studies investigated the possibility to obtain active systems by
means of well-assessed industrial processes, such extrusion (177). Del Nobile and
colleagues compared the performances of synthetic recyclable systems (based on
low density polyethylene) with biodegradable ones (PLA and PCL). They used
an industrial process (twin-screw extruder) to prepare films and tested the effect
of the manufacturing conditions on the antimicrobial effectiveness of films loaded
with natural compounds. They found that the processing temperatures play a ma-
jor role in determining the antimicrobial efficiency of the investigated active films.
In particular, PLA and LDPE-based systems retained slight antimicrobial activ-
ity, whereas PCL ones, due to the much lower processing temperatures, allowed
less degradation of antimicrobial activity.
Studies on the biodegradability of a blend of PCL with nonbiodegrad-
able polymers were conducted by Iwamoto and Tokiwa (178). They found that
PCL/polyolefin blends could also be a viable solution for food packaging because an
enzymatic degradation of the blend, either PCL/LDPE or PCL/polypropylenede,
can occur if viscosity and formulation are properly designed. Furthermore, they
inferred from the phase structure of the blend that it is the continuous phase of
PCL that is responsible for the degradability of the blend.
A more complex morphology for films is constituted by porous PCL films.
They can be prepared by removing, typically by means of a specific solvent, a
nonmiscible dispersed phase (179). The presence of porosity increases the surface
exposed to enzymatic degradation and also increases permeability to gaseous or
vapor species, both properly tailored by the proper choice of particle size distribu-
tion.
5.5. Reinforced PCL Composites. In general, materials based only on
PCL are not used in applications where structural performances are required due
to its limitations in glass transition temperature (< –60 ◦ C) and elastic properties
(Young’s modulus around 0.5 GPa). Although it is a semicrystalline polymer, hence
it can be used above its Tg , the elastic modulus is quite low when compared to
other biodegradable polymers such PLA or polyhydroxybutirrate (PHB). A viable
and effective method to improve the stiffness of PCL, and to increase its potential
usability in load-bearing applications, is to reinforce it or, better, use one of its
blends, with high aspect ratio fillers, such as short fibers or fabrics. In particular,
since PCL is highly biodegradable, a lot of efforts have been put in investigating
PCL composites reinforced with natural fibers (180,181).
The term natural fibers can point to either organic (flax, hemp, cellulose,
ramie) or inorganic (hydroxyapatite, basalt, glass) fibers. They are very abun-
dant in nature, can be biocompatible or bioresorbable, renewable and sustainable,
and can allow reaching a high performance over cost ratio. In the following, the
term natural fibers will be used to refer to organic fibers, which possess a much
higher strength per unit weight than most inorganic fillers, lower density, and
their biodegradable nature make natural fillers attractive as reinforcements for
engineered biodegradable polymeric systems (67,182,183).
Since the high hydrophilicity of natural fibers, some drawbacks are present,
such their incompatibility with the hydrophobic polymer matrix, the tendency to
form aggregates during processing, and the poor resistance to moisture. These
issues greatly reduce the potential of as is natural fibers as reinforcements, but
specific surface treatments through physical and/or chemical processes for the
improvement of fiber–matrix interaction can be exploited to improve fiber wetting
and hence the structural performance of PCL composites (Fig. 10).
Chemical modification of natural fibers was the first approach to increase
the adhesion between the hydrophilic fibers and hydrophobic matrix (184–186).
Even if the most promising way is to directly induce covalent bonds between fiber
and matrix, the difficulties in finding affordable and controllable processes of this
type leave room for other, simpler solutions. Alkali treatment is a well-known
process; it is used from long time and allows to treat almost all the natural fibers
with effective and good results. Another well-known treatment is with the use of
maleated coupling agents, widely used for polyolefins because the interactions be-
tween the anhydride groups of maleated coupling agents and the hydroxyl groups
of natural fibers can effectively improve the adhesion between fiber and matrix.
Silane-coupling agents are also used, but they are not suitable for all polymers;
and some authors reported the need to use high temperatures to obtain a satisfy-
ing coupling. Coupling agents from natural resources have also been investigated
such as lignin (successfully used in hemp and jute fiber composites), chitin and
chitosan (used in wood-flour composites), fungus, or proteins (zein was used with
very promising results).
Albeit the properties of natural fiber reinforced polymer composites are gen-
erally governed by the pretreatment process of fibers and the manufacturing pro-
cess of the composites, the complexity and variability of fiber structures can lead to
variability in the mechanical performances of composites with the use of the same
Fig. 10. (a) Fracture surface of tensile specimens of flax/PCL composites. (b) Fracture
surface of tensile specimens of flax/PCL-g-MA compatibilized composite (Reprinted with
permission from Ref. 193. Copyright 2006 Elsevier).
fiber type in different production batches (187). Unlike for synthetic fibers, in fact,
the fiber/matrix interface strength, the fiber impregnation, and the bonding can
change along the natural fiber due to the uneven geometry or local composition.
Furthermore, some processes are not targeted for natural fibers, but have been de-
veloped for the fast and reliable production of synthetic composites. Such issues
should be taken into account in the design of a biodegradable composite because
they can lead to lower than expected performances.
In structural applications often PCL is blended with other polymers with
higher glass transition temperature. PLA/PCL composites were developed by Xu
and co-workers by using ramie fiber by means of the in situ polymerization method
(188). They treated the ramie fibers with a silane-coupling agent to increase the in-
terfacial interactions with the polymeric blend. The compatibilized systems exhib-
ited better mechanical properties (strength and impact resistance) with respect to
composites prepared with untreated fibers. They also found that high ramie fibers
content, and fibers as long as 6 mm had to be used to maximize performances.
Several works are present reporting on the mechanical behavior of compos-

ites based on PCL/starch blends reinforced with sisal fibers (189–191). In this
case, the mechanical performance was improved after a specific alkaline surface
treatment of sisal fibers. A commercial widely used biodegradable matrix based
on PCL and starch was used (Mater-Bi-Z). The treatment improved the adhesion
and the compatibility of the fibers and allowed a sound improvement of the elastic
modulus and strength.
A PCL/starch blend has been used to prepare composites reinforced with ke-
naf and bamboo fibers, compatibilized with an alkali treatment by Shibata and
others (192). The authors measured an increase of the flexural modulus with in-
creasing fiber content. They tried to model the mechanical behavior of the pre-
pared composites with the Cox’s model but failed to correctly predict the perfor-
mance of composites based on bamboo fibers. They found that this issue came
from the difficulties in measuring the mechanical properties of fibers, which ex-
hibited unreliable failure point. They were successful in getting composites with
good flexural modulus, but pointed out that segregation of the polymer during the
production process could occur in some reinforcement configurations, thus result-
ing in low mechanical performances.
PCL/flax fiber composites were produced by Arbelaiz and colleagues by using
maleated-coupling agents to prepare a poly(𝜀-caprolactone)-grafted-maleic anhy-
dride copolymer (PCL-g-MA) as a compatibilizer intended to increase the interac-
tions between matrix and fibers (193). The grafting reaction of maleic anhydride
(MA) onto PCL polymer was carried out in the presence of dicumyl peroxide as
an initiator. Composites fabricated with flax fiber bundles and PCL-g-MA matrix
showed very high tensile and flexural strengths, as a consequence of the improved
fiber/matrix adhesion (Fig. 10). A potential drawback of using a compatibilizer is
the effect on the crystallinity. In fact, both mechanical properties and crystallinity
of composites decreased with the addition of small amounts of PCL-g-MA cou-
pling agent. Crystallinity reduction was considered the possible reason for lower
mechanical properties in some cases; hence, a proper increase of mechanical per-
formance can be obtained by using proper amounts of compatibilizer, to maximize
the interactions of the polymer with fibers and to recover some crystallinity.
The effect of fibers on the biodegradability can also arise (194). Natural
fiber/polymer composites are usually intended for being used in nonload bear-
ing, indoor, and low shelf life components due to their intrinsic vulnerability to
environment. Nevertheless, some industrial fields require biodegradable compos-
ites to replace conventional, nondisposable ones. This implies that they have to be
used in applications where such composites are exposed to moisture, thermal, fire,
and ultraviolet degradation. Large fiber content provides strength to the polymer
composite, but it also becomes an entry point for moisture attack. For this reason,
several fiber treatments are developed to improve fiber/matrix interface and mois-
ture durability. However, treated fibers were found to behave poorly when exposed
to weather and UV stabilizers, and fire retardants must be used to increase out-
door usability and fire performance. These additives can compromise the strength
of composites. A balance between strength and durability has to be accepted for
using natural fibers in low demanding structural applications (195).
Natural composites based on PCL have been investigated by Wahit and
co-workers, who reported that green composites with enhanced mechanical
properties and biodegradation were prepared (196). Composites were prepared

using various fiber treatments, and most of them proved to be effective in prop-
erty enhancement, thereby raising the potential of natural fiber–based compos-
ites in outdoor applications. The optimum mechanical properties for most of the
composites were obtained at an average fiber load of 30%. The authors pointed
out that the use of fibers also allowed to reduce the cost of such green compos-
ites and hence expanding their application areas. Di Franco and co-workers pro-
duced composites with sisal fibers and PCL/starch matrix (197). The analysis of
the hydrolytic stability of both composites and unfilled matrix showed that the
use of fibers resulted in a promoted entrance of water, with a consequent swelling
and hydrolysis of the starch phase. High fiber content should be reached to get a
higher hydrolytic stability, but this probably was due to the presence of a fiber–
fiber physical network. Microbial attack in biotic aqueous medium was evidenced
by the presence of a biofilm, especially on the fiber surface. The presence of fibers
indirectly promoted the degradation of PCL/starch in biotic environments, since
they serve as support for the attack of the microorganisms and favored water
entrance.
The thermal degradation behavior of composites made of TPS, PCL, and
bleached sisal fibers was investigated by thermogravimetry analysis. The au-
thors showed that at 5 wt% sisal fiber loading the apparent activation energy
and the melting temperature of the composites decreased when compared with
the TPS/PCL blend. A further increase of sisal fibers showed to increase the acti-
vation energy of composites thus improving their thermal stability (198).
6. Conclusions
The successful use of PCL and its copolymers in different application fields, rang-
ing from biomedical science to eco-sustainable materials, clearly indicates their
suitability for the fabrication of promising platforms with long-term degradation.
The easy manipulation of PCL physical, chemical, and biological properties facil-
itates tailorable degradation kinetics needed to target the peculiar features of a
specific anatomical site. Moreover, extensive in vivo studies performed on the bio-
compatibility, degradation behavior, and biomechanical properties of PCL enabled
the acquisition of important certifications, such as FDA approval and CE Mark
registration, which are mandatory for the commercialization of smart devices for
different clinical uses as well as for packaging and composites applications. How-
ever, the route for a rapid commercialization of new products to the market is still
long. In perspective, more efforts are needed to provide a faster translation of tech-
nology from laboratories to clinical trials. This will enable to extend the current
information libraries, mainly based on proof-of-principle or partial studies, while
expediting the scale-up and marketing of different biomedical products—that is,
suture wires, wound dresses, artificial blood vessels, nerve conduits, drug-delivery
devices, bone engineered scaffolds, and biobased composite and packaging appli-
cations.
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Glossary
CAD Computer-aided design

CALB Candida Antarctica Lipase B
DCM Dichloromethane
DPavg Average polymerization degree
FDA Food Administration Approved
MDO 2-Methylene-1,3-dioxepane
O/O Oil in oil
O/W Oil in water
PCL Polycaprolactone
PCL-g-MA Poly(𝜀-caprolactone)-grafted-maleic anhydride
PDS Polydioxanone
PEO Poly(ethylene oxide)
PGA (- DexonTM Polyglycolic
PHB Polyhydroxybutirrate
PLA Poly(lactic acid)
RAFT Addition-fragmentation chain transfer
ROP Ring-opening polymerization
RROP Radical ring-opening polymerization
SPI Soy protein isolate
TIPS Thermal induced phase separation
Tm Melting temperatures
TPS Thermoplastic starch
TPZ Thermoplasticized zein
Vicryl R⃝ Polylactic-polyglycolic acid (PLGA 10/90 - Vicryl R⃝ )PLLGA
10/90
W/O Water in oil
W/O/O Water in oil in oil
VINCENZO GUARINO
GENNARO GENTILE
LUIGI SORRENTINO
Institute for Polymers, Composites and
Biomaterials, National Research Council, Naples,
Italy
LUIGI AMBROSIO
Institute for Polymers, Composites and
Biomaterials, National Research Council, Naples,
Italy and Department of Chemicals Science and
Materials Technology, National Research Council,
Rome, Italy

Polycaprolactone: Synthesis, Properties, and Applications

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POLYCAPROLACTONE: SYNTHESIS, PROPERTIES, AND

Polycaprolactone (PCL) is a polymer composed of hexanoate repeat units, included

The first synthesis of PCL by thermal treatment of 𝜀-caprolactone was reported

Fig. 1. Synthetic routes to PCL by ionic or metal-catalyzed ROP of 𝜀-caprolactone, by

relevant phenomenon, because, depending on the experimental conditions, up to

Cationic ROP (Fig. 3b) is based on the attack of a cation to 𝜀-caprolactone

Fig. 4. Representative advanced polymeric architectures employing PCL segments. PCL

copolymers to crystallize and to their large structural disorder. The copolymers

4.1. PCL Melting Processes. Extrusion is the most used technology

3. gas injection and solubilization (in case foams have to be produced),

dispersed in aqueous media—oil in water (O/W)—or by water-soluble monomers

5.1. Scaffolds for Tissue Engineering. Tissue engineering strat-

tissue engineering because of their good biocompatibility and processability. In

the regeneration process of hierarchically organized tissues (ie, tendons, muscles,

chitosan resulted in an increase in elongation by 20.56% as compared to the pure

Several works are present reporting on the mechanical behavior of compos-

properties and biodegradation were prepared (196). Composites were prepared

1. L. S. Nair and C. T. Laurencin, Prog. Polym. Sci. 32, 762–798 (2007),

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CAD Computer-aided design

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