Polymer Degradation and Stability 130 (2016) 118e125

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Polymer Degradation and Stability

journal homepage: www.elsevier.com/locate/polydegstab

A comparative study on Poly(ε-caprolactone) film degradation at

extreme pH values

zar a, *
G. Patricia Sailema-Palate a, A. Vidaurre a, b, A.F. Campillo a, I. Castilla-Corta
a
Centro de Biomateriales e Ingeniería Tisular, Universitat Polit
ecnica de Val
encia, 46022 Valencia, Spain
b
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Valencia, Spain

a r t i c l e i n f o a b s t r a c t

Article history: The present paper studies the effect of pH on hydrolytic degradation of Poly(ε-caprolactone) (PCL)
Received 19 April 2016 Degradation of the films was performed at 37
C in 2.5 M NaOH solution (pH 13) and 2.5 M HCl solution
Received in revised form (pH 1). Weight loss, degree of swelling, molecular weight, and calorimetric and mechanical properties
30 May 2016
were obtained as a function of degradation time. Morphological changes in the samples were carefully
Accepted 5 June 2016
Available online 7 June 2016
studied through electron microscopy. At the start of the process the degradation rate of PCL films at pH
13 was faster than at pH 1. In the latter case, there was an induction period of around 300 h with no
changes in weight loss or swelling rate, but there were drastic changes in molecular weight and crys-
Keywords:
PCL
tallinity. The changes in some properties throughout the degradation period, such as crystallinity, mo-
Hydrolytic degradation lecular weight and Young’s modulus were lower in degradations at higher pH, highlighting differences in
pH the degradation mechanism of alkaline and acid hydrolysis. Along with visual inspection of the degraded
Hydrolysis samples, this suggests a surface degradation at pH 13, whereas bulk degradation may occur at pH 1.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction counterparts, which renders it easy to manufacture and manipulate

into a large range of scaffolds. Surprisingly, despite more than 1000
Polycaprolactone (PCL) is a bioabsorbable, semi-crystalline papers being published during the last decade in the biomaterials
polymer (Tm z þ60
C) with a low glass transition temperature and tissue-engineering literature on PCL-based-scaffolds, only a
(Tg z 60
C), which can be degraded by microorganisms, as well small number of groups have included a study of the degradation
as by hydrolytic mechanisms under physiological conditions [1]. and resorption kinetics of PCL scaffolds [6].
Because of its low glass transition temperature, the PCL amorphous The most important role of the use of scaffold in vivo is that it
phase displays high molecular mobility at body temperature. In persists in a robust state for sufficient time to allow the formation
comparison with the other commercially available bioresorbable of new tissue, but also ultimately degrades and is replaced by this
polymers, PCL is one of the most flexible and easy to process ma- tissue. Hydrolytic degradation is of crucial importance [7,8] for its
terials [2]. Because of its significant degree of crystallinity and successful implementation in applications such as surgical sutures,
substantial hydrophobicity, high molecular weight PCL has shown drug delivery systems, and tissue engineering scaffolds. The rate of
remarkably long in vivo degradation times, in some instances as degradation has been attributed to a number of polymer charac-
long as 2 years [3]. As for its tissue compatibility, PCL is known to teristics. It is believed that the access of water to the ester bond,
elicit a rather mild inflammatory response [4]. rather than intrinsic rates of ester cleavage, govern the time it takes
Polycaprolactone (PCL) was one of the earliest polymers syn- for a polymer to degrade [9]. Water access to the ester bonds is
thesized by the Carothers group in the early 1930s [5] and a determined by the combined effect of the hydrophobicity of the
resurgence of interest during the 1990s and 2000s has stemmed monomers, the crystallinity of the sample, the molecular weight,
from the realization that PCL possesses superior rheological and the glass transition temperature and the bulk sample dimensions
viscoelastic properties over many of its resorbable-polymer [10e12]. Some studies have also shown the effect of porosity on
degradation of PCL samples [13,14] and on degradation of samples
based on other polyesters [15,16]. High porosity with a large spe-
cific surface could increase the hydrolysis rate and produce large
* Corresponding author. amounts of acid byproducts and also provide a better inter-

zar).
E-mail address: icast@fis.upv.es (I. Castilla-Corta

http://dx.doi.org/10.1016/j.polymdegradstab.2016.06.005
0141-3910/© 2016 Elsevier Ltd. All rights reserved.
 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125 119

connective pore structure and enhanced fluid permeability [14]. 2.2. Methods
Natu et al. have shown that the processing method does not have a
significant effect on the long term degradation of PCL constructs, 2.2.1. Incubation
although there were some differences in the degradation profile for The resultant films were cut into discs (diameter, 6 mm; thick-
samples prepared by different processing methods of up to 18 ness, 2.5 mm) and used for the degradation experiments. After
months, these differences tended to disappear during the advanced placing the films (z70 mg) into test-tubes, degradation solution
stage (18e36 months) [17]. was added at either pH 1 or pH 13; the ratio sample/degradation
A closer look at the degradation of polyester materials has medium was 1/50 in mass. Triplicates were prepared for each
revealed that there are still many unsolved problems that hinder us period of degradation for both pH settings to minimize the effects
from taking full advantage of these materials [18]. Most of what we of random errors. After the addition of degradation solution, the
know about degradation mechanisms dates back to the early 1980s, test tubes were placed in an oven at 37.0
C for incubation. At
when degradable polymers were classified into surface eroding and predetermined time intervals three sample replicates were taken
bulk eroding [19]. Several mathematical models have been devel- out of the solution, washed twice with distilled water, wiped,
oped to predict the degradation of the aliphatic polyesters in an weighed, and subsequently vacuum dried prior to posterior
aqueous environment [18,20e23]. analyses.
The degradation rate also depends strongly on pH. However
most degradation studies are usually done in a physiologic saline
solution of pH 7.4. After shifts in pH, reaction rates of esters may 2.2.2. pH
change some orders of magnitude due to catalysis. Ester hydrolysis The pH measurements in the degradation medium were carried
can therefore either be acid or base catalyzed [24]. It is therefore out using a pH meter equipped with an Ag/AgCl electrode with an
important to understand the pH dependent degradation of bio- accuracy of ±0.01 (XS instruments 510). The instrument was cali-
materials, because they should be able to retain adequate proper- brated using buffer solutions at pH 4 and pH 7.
ties under all possible physiologic and pathologic conditions. It is
known that the pH of gastric juice in the stomach can go as low as
0.9e1.5, while the pancreatic juice in the duodenum ranges from 2.2.3. Porosity
7.5 to 8.2 [25]. Hydrolytic degradation of Poly(glycolic acid) has Sample porosity (4) before immersion in degradation solutions
been reported at three different pHs [26]. The comparison of the was estimated from the apparent volume VT and PCL volume VM,
effect on mechanical properties of pH levels ranging from 5.25 to defined by the actual amount of polymer (m) and its mean density
10.09 on the hydrolytic degradation of polyglycolic acid and (r) (r ¼ 1.14 g/cm3)
poly(glycolide-lactide) suture materials has also been reported
[25]. Accelerated degradation studies in an alkaline medium have VT  VM VT  m
r
previously been reported by a small number of groups for PCL- 4ð%Þ ¼  100 ¼  100
VT VT
based polymeric films and devices [27e30]. Tsuji and Ishizaka
studied the enzymatic and alkaline degradation of porous PCL films Ten replicates were used to obtain mean porosity and standard
[31]. The degradation of PCLs in acidic and basic media have been deviation (SD).
studied by Jung et al., who reported variations in the relative vis-
cosities at various pH as a function of time [32].
The objective of this study is to further investigate the hydrolytic 2.3. Degree of swelling and weight loss
degradability of PCL films by assessing the effects of extreme pH (1
and 13) on weight loss, degree of swelling, molecular weight, and The degradation process was followed by determining the water
calorimetric and mechanical properties, as well as morphological absorption and mass loss of the materials. Samples were washed
changes, to better understand the influence of the pH medium on with distilled water and gently wiped with paper. Wet weight was
the process of degradation and the relationship between bulk and determined in order to evaluate the evolution of the samples’ hy-
surface characteristics during the degradation period. drophilicity. The degree of swelling was determined by comparing
the wet weight (ww) at a specific time with the dry weight (wd)
according to Eq. 1

2. Materials and methods ww  wd

degree of swelling ð%Þ ¼  100 (1)
wd
2.1. Materials
The percentage of weight loss was determined after drying the
samples in a vacuum by comparing dry weight (wd) at a specific
2.1.1. Poly(caprolactone) films
time with the initial weight (w0) according to Eq. 2
(PCL) [Polysciences (Mw 43,000e50,000)] in the form of powder
was used without further purification. The solvent, tetrahydrofuran w0  wd
(THF) from Aldrich was used as received. Films were prepared from weight loss ð%Þ ¼  100 (2)
w0
a solution of PCL in tetrahydrofuran (THF) by evaporation of THF at
room temperature (for 7 days). A balance (Mettler Toledo) with a sensitivity of 0.01 mg was
used to weigh the samples.

2.1.2. Degradation solutions 2.4. Scanning electron microscopy (SEM)

Sodium hydroxide, NaOH, and hydrochloric acid, HCl, from
Sharlab were used as received. Distilled water with 10 mS conduc- To investigate the surface and cross section morphology of dried
tivity was used as a solvent. 2.5 M degradation solutions were samples, SEM pictures of degraded and non-degraded samples
prepared from HCl (pH 1), and NaOH (pH 13). were taken using a JEOL JSM-5410 scanning electron microscope.
120 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125

2.5. Molecular weight analysis by gel permeation chromatography swelling, reaching a maximum value of around 10% for a period of
(GPC) 150 h and then remained almost constant for the rest of the time
interval. It was not possible to handle the samples after 1500 h of
The weight average molar mass of the samples was determined degradation to measure the degree of swelling due to fragmenta-
with a gel permeation chromatographer at 30
C using a Waters tion. For films degraded at pH 1 the water uptake had an induction
Breeze GPC system with a 1525 Binary HPLC pump (from Waters period in which the degree of swelling did not significantly change.
Corporation, Milford, MA) equipped with a 2414 refractive index After 380 h, water absorption increased steadily, reaching 80% at
detector and Waters Styragel HR THF columns. THF was used as the the end of the degradation period (2250 h). The degree of swelling
eluent at a flow rate of 0.5 mL/min. The calibration curve was as a function of weight loss is shown in Fig. 2. Films degraded at pH
prepared by using monodisperse polystyrene standards from 1 exhibited a linear relationship between both parameters
Shodex (Showa Denko K.K., Kawasaki, Japan). (r2 ¼ 0.9934). However, at pH 13 the degree of swelling slightly
increases at the beginning of degradation with no significant
2.6. Differential scanning calorimetry (DSC) changes during the rest of the degradation process.
The extent and mechanism of hydrolysis are determined by the
The thermal properties of the samples were measured by using amount, presence and location of water molecules. Thus, the
a Mettler Toledo differential scanning calorimeter (DSC) calibrated polymers’ chemical composition, hydrophobicity, size and design
with indium. The measurements were carried out at a scan rate of all play an important role in this interaction with water [28]. The
10
C/min between 10
C and 100
C. Crystallinity was calculated differences in the degradation behavior at different pH can be
assuming proportionality to the experimental heat of fusion, using correlated with the effect of pH on hydrophilicity. The polymer at
the reported heat of fusion of 139.5 J/g for the 100% crystalline PCL alkaline pH (pH 13) maintains its apolar (hydrophobic) character,
[33]. probably because hydroxyl ions are entrapped by the ester groups
on the film surface, which lowers its absorption capacity. As a
2.7. Mechanical testing result, water cannot penetrate the sample and the weight loss can
only be produced by superficial degradation. However, at acid pH
A monotonic ramp performed at a 0.01 mm/s cross-head ve- the PCL films change from hydrophobic to hydrophilic in character
locity was carried out using an Instron MicroTester 5548 machine during the stay in the degradation solution. The absorption capacity
with a precision of 0.0001 N and 0.001 mm in force and displace- increases linearly with weight loss. Larger water uptake results in
ment respectively, provided with a 50 N load cell. The dimensions an increased hydrolysis rate as more water penetrates the samples.
of the sample were measured before and after the test. Five repli-
cates for each degradation time were measured. Experiments were 3.3. Visual examination and scanning electron microscopy (SEM)
performed at room temperature.
Before hydrolysis all the films were homogeneous and had a
3. Results and discussion smooth and even surface structure. After degradation, samples
immersed in acid or basic medium exhibit quite different mor-
The degradation process of aliphatic polyesters is based on a phologies (Fig. 3a) and b)). Films degraded at pH 13, see Fig. 3a,
hydrolytic cleavage of the ester bonds on their backbone chains present non-uniform superficial erosion. After 168 h of degrada-
[34]. When the water molecules attack the ester bonds in the tion, mass loss is only 10.6% and to the naked eye presents a rough
polymer chains, the average length of degraded chains becomes surface with small cavities. After 621 h, when the sample has lost
shorter. Eventually, the process results in short fragments of chains 62.5% of its mass, large cavities can be observed on the disk surface.
that become soluble in water. There are reports in the literature that This effect is much higher when the sample has lost 92% of its mass.
indicate that molecular weights that are suitable for renal clearance In contrast, the films degraded at pH 1, see Fig. 3b, showed an in-
are in the range of 10e50 kDa [35,36]. crease in opacity during the course of the degradation experiment
and slowly began to decrease in size after 120 h of degradation.
3.1. Porosity After 600 h of degradation, cavities, cracks and fissures appeared,
which is consistent with bulk degradation. The whitening observed
Mean sample porosity and SD before immersion in degradation during hydrolysis is assumed to be an effect of molecular reorga-
solution was 14.90 ± 0.56%. This result is in agreement with [13], in nization during degradation and has previously been concluded to
which sample morphology was observed by SEM. be the result of the formation of accelerated spherules in lactic acid
based polymers [37,38]. However, surface roughening and the for-
3.2. Weight loss and degree of swelling mation of small pores/fissures, as shown by the SEM analysis, will
also lead to scattering of light and whitening of the samples.
The weight loss profile measured in PCL films at 37
C as a Fig. 4 shows the SEM microphotographs of degraded samples
function of time is shown in Fig. 1 (left). The specimens degraded at with similar weight loss (close to 50%). The sample degraded 317 h
pH ¼ 13 showed a faster rate of degradation than those degraded at at pH 13 is shown in Fig. 4 (left) and presents a porous structure.
pH 1. At pH 13 it is apparent that there were two weight loss rates. The insets contain enlargements. Large cavities can be seen
From 0 to 600 h, when the weight loss is approximately 60%, a more together with increasing surface roughness. Fig. 4 (right) shows the
or less linear and steep degradation profile was observed, after PCL sample after 909 h at pH 1. It can be seen that the surface is
which the degradation process slowed down. The weight loss was covered with cracks with small pores.
around 98% at 2110 h. The weight loss of the samples degraded at
pH 1 presented a clear induction period of around 300 h, after 3.4. Molecular weight analysis (GPC)
which the mass decreased continuously to a weight loss of around
97% after 2300 h. The changes in molecular weight for the two different degra-
The degree of swelling shows a different tendency for the dations, at extreme pH, presented different behaviors (Fig. 5). At
samples degraded at different pH values (see Fig. 1, right). Samples basic degradation of pH 13, it is observed that the molecular weight
degraded at pH 13 showed an initial increase in the degree of distribution remains unchanged with time; this phenomenon can
 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125 121

Fig. 1. Weight loss profile (left) and degree of swelling (right) as a function of degradation time. Error bars represent standard deviation.

be related to erosive degradation [39]. Despite the weight loss of

the sample, the core material remains intact and the molecular
weight distribution remains constant with time.
On the other hand, in the pH 1 acid medium, the molecular
weight distribution is seen to move towards lower values and a
double peak distribution is present after 909 h of degradation.
Similar behavior of the dependence of the molecular weight dis-
tribution has also been found by other authors [40e42].
Surface degradation takes place when diffusion is much slower
than the degradation of the polymer bonds. Water penetrates into
the polymer at a slower rate than hydrolysis; the hydrolysed sur-
face by-products simply diffuse rapidly into the media and there is
no opportunity for water molecules to reach the center of the
matrix. Degradation occurs purely at the surface. As a consequence,
the polymer device experiences a thinning effect and leaves the
Fig. 2. Degree of swelling as a function of weight loss. Straight line represents the molecular weight intact, since lower molecular weight surface by-
linear fit of data corresponding to pH 1. products are diffused out [28].

Fig. 3. Photographs of samples at different degradation time for samples immersed in a) basic pH 13 and b) acid pH 1 media. Labels indicate degradation time in hours and
percentage weight loss.
122 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125

Fig. 4. Superficial SEM microphotographs of samples at different degradation times for samples degraded at pH 13 after 317 h and 47% of weight loss (left) and at pH 1 after 909 h
and 49% of weight loss (right). The insets show a higher magnification (bar ¼ 10 mm).

Fig. 5. Molecular weight distribution vs. time degradation in acid medium pH 1(left) and in basic medium pH 13 (right).

Bulk degradation occurs when the diffusion of water into the differences between the calorimetric scans throughout degrada-
polymer is faster than the degradation of polymer bonds. The tion. These results, together with the fact that there was no sig-
medium is able to penetrate through the entire polymer and nificant change in molecular weight, are consistent with surface
random hydrolytic chain scissions take place throughout the matrix erosion, since DSC curves for different times showed very little
in a more or less uniform manner. The common hydrolyzed by- difference and the crystallinities of the PCL films did not change.
products of polyester degradation are typically the hydroxyl and The comparison of weight loss and crystallinity indicates that both
carboxyl end groups. As a result, the formation of these end groups the amorphous and crystalline phase samples degraded in a similar
from each ester-bond cleavage produces carboxylic acid, which is a way to enzymatic degradation [43,44].
catalyst for hydrolysis [28]. When these by-products are removed Thermal analysis of films, at pH 1 showed a 24% increase (from
from the polymer matrix, chain scission becomes homogeneous; 67 to 88%) in the degree of crystallinity (cc) during the degradation
this principally defines bulk degradation when molecular weight period. After reaching 88% crystallinity, there is little change in the
reduction is homogeneous. In contrast, when these by-products are remaining period of degradation. This rise can mainly be related to
not able to diffuse out of the polymer matrix, they form a con- the degradation of the amorphous phase. Besides, when the poly-
centration gradient of carboxylic acid from the center to the surface mer chains are short enough, the increased mobility of the chains
of the polymer producing an exponential rate of degradation at the makes it possible for them to reorganize and crystallize [40,45]. The
core of the material. This phenomenon is known as internal auto- melting temperature for films degraded at pH 1 decreased (from 66
catalysis, which produces a bimodal molecular weight distribution to 64
C) as a result of the formation of smaller crystals of shorter
[40]. polymer chains [46].
Other degradation studies of different aliphatic polyesters at
different pH [47,48], have shown higher degradations rates in
3.5. Differential scanning calorimetry (DSC)
alkaline solution than degradation under acidic conditions, where
the rate was comparable to that in neutral buffered solutions
The changes in thermal properties during degradation were
[49,50].
monitored by differential scanning calorimetry (DSC) (see Fig 6).
The degree of crystallinity (cc) and the melting temperature (Tm)
were determined during the first heating scan. The thermal anal- 3.6. Mechanical testing
ysis of films degraded at pH 13 showed no significant change in
crystallinity(cc), which was only 2% higher after 553 h of degra- The controlled decline of mechanical properties is desirable as
dation (Table 1). At longer degradation times, the melting tem- tissue regeneration progresses; it is believed that the ideal in vivo
perature increased slightly, from 66
C to 68
C. There were no degradation rate is equal to or slightly less than the rate of tissue
 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125 123

Fig. 6. Endothermic DSC curves for the first scan in acid medium, pH 1 (left) and basic medium pH 13 (right).

Table 1 relationship [55]. Samples degraded for longer than 500 h at pH13
Crystallinity and melting temperature determined during the first scan for the were very difficult to handle and no mechanical measurements
degraded samples at pH 13 and pH 1.
were possible.
pH 13, 1st scan pH 1, 1st scan Our results obtained at acidic pH 1, with significant mass loss
t (h) c(%) Tm (
C) t (h) c(%) Tm (
C) and increased water uptake during the degradation period,
together with the molecular weight results and morphology data,
0 66 66 0 67 67
165 66 67 173 72 66 seem to be clearly related to bulk erosion. As we have mentioned
390 68 67 909 88 62 above, when water penetrates into the material it causes erosion
553 68 68 1797 88 64 that affects the whole solid mass. Initially the degradation starts at
the amorphous phase, with reduction in molecular weight but
without any loss in physical properties. After the induction phase,
formation [51]. the molecules become water soluble, initiating the mass loss of the
Fig. 7 exhibits the Young’s modulus of films degraded at pH 13 polymer. In contrast, the results of the degradation at basic pH 13 in
and pH 1. Non degraded films presented an initial Young’s modulus molecular weight, mass loss and water uptake, DSC, together with
of 12 MPa. During the degradation period the PCL samples showed the morphology data, are consistent with the fact that degradation
a rapid decrease in the modulus over time at both pHs. The same proceeds from the surface to the interior of the sample. As far as we
value of Young’s modulus (5 MPa) was reached after 600 h of know these results of the degradation of PCL films at extreme pH
degradation at pH 1, when the mass loss was 25%, and after 500 h of have not previously been published. In the literature, the majority
degradation at pH 13, when the mass loss was 55%. The drop in the of the studies on the degradation of polyesters are focused on PLA
Young’s modulus of the samples can be related to the increased and its copolymers, which means that the theory of the hydrolytic
porosity due to degradation. The dependence of mechanical degradation mechanism of polyesters is mainly based on the results
properties on sample porosity has been reported by Thomson et al. of PLA degradation [22,37e40,43]. Our results with PCL samples
[52] and de Groot et al. [53]. More recently, other groups [2,54] have corroborate the findings of Von Burkersroda et al. [18] for PLA and
demonstrated the dependence of mechanical properties on scaffold our data therefore provide experimental support for their theory
porosity when fabricating scaffolds via rapid prototyping. Logically, that a polymer considered bulk eroding according to the literature
as porosity increases the mechanical properties should deteriorate can be made surface eroding. These authors consider the three
correspondingly. This decline has been found to follow a power law main parameters that determine the erosion mechanism: water
diffusivity, reactivity of polymer with respect to hydrolysis and the
dimension L. In our case, the sample size was below the critical
dimension of 1.3 cm for PCL obtained by Von Burkersroda et al. [18],
from the literature [56]. The change of the erosion mechanism was
induced by the change of reactivity with pH.
To summarize, from our results on weight loss and degree of
swelling (Figs. 1 and 2), molecular weight profiles (Fig. 5) and the
morphology data (Figs. 3 and 4), it can be deduced that the
degradation pathways proceeded via the surface degradation
mechanism at pH 13 and via bulk degradation mechanism at pH 1.
Lam et al. [28] studied long-term degradation of PCL scaffolds using
phosphate-buffered saline (PBS) at pH 7.4 and found a bulk
degradation pathway. Accelerated degradation aims to degrade
polymeric devices in a shorter period of time and could be achieved
by an acidic or basic medium. Our results also show that acceler-
ated degradation in acidic media better matches degradation in
phosphate buffered saline (PBS) at pH 7.4.

Fig. 7. Young’s modulus of films degraded at pH 13 and pH 1 as function of degra-

dation time.
124 G.P. Sailema-Palate et al. / Polymer Degradation and Stability 130 (2016) 118e125

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