combining biodegradation, controlled drug release and shape memory effect

8/10/2019 Combining Biodegradation, Controlled Drug Release and Shape Memory Effect

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Crosslinked poly(e-caprolactone)/poly(sebacic anhydride) composites

combining biodegradation, controlled drug release and shape memory effect

Yu Xiao, Shaobing Zhou *, Lin Wang, Xiaotong Zheng, Tao Gong

School of Materials Science and Engineering, Key Laboratory of Advanced Technologies of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu 610031, PR China

a r t i c l e i n f o

Article history:Received 5 March 2010

Received in revised form 7 June 2010

Accepted 10 July 2010

Available online 16 July 2010

Keywords:

A. Polymermatrix composites (PMCs)

A. Smart materials

B. Stress relaxation

D. Mechanical testing

a b s t r a c t

In this study, we investigated the shape memory effect and drug release behavior of a biodegradablepolymeric composite consisted of crosslinked poly(e-caprolactone) (cPCL) and poly(sebacic anhydride)

(PSA). This composite was prepared by a solution-casting method. The drug delivery system was applied

to cooperate with the shape memory property in the biodegradable polymeric composites for the first

time. The effect of PSA addition on the mechanical, shape memory, in vitro degradation and drug release

behavior was studied by static tensile test, dynamic mechanical analysis (DMA), FT-IR and degradation

evaluation, etc. In vitro degradation and drug release results showed that the degradation speed of cPCL

and the release accumulation of drug could be enhanced by adding PSA into cPCL matrix. The multifunc-

tional polymer composite has great potential as drug eluting stents in biomedical field.

2010 Elsevier Ltd. All rights reserved.

1. Introduction

Shape memory polymers (SMP) are drawing more and more

attention due to their fantastic properties and potential applica-

tions in recent years, especially in the biomedical field [1,2]. What

makes SMP superior to shape memory alloys and ceramics is large

recoverable strain, low energy consumption, excellent manufactu-

rability and bio-degradability[35]. However, with the increasing

and much more complex requirements, the single-functional SMP

have not fulfilled their technological use [1,2,6]. Therefore, we

need some multifunctional SMP[7].

In fact, the multifunctional SMP that combine two functions

such as shape memory effect and bio-degradability or shape mem-

ory effect and drug release have been already realized [814].

However, the SMP that combine three above functions have not

yet been demonstrated. In this study, we firstly added the

poly(sebacic anhydride) (PSA) into the poly(e-caprolactone) (cPCL)

matrix to prepared a new kind of multifunctional SMP. In view of

the wonderful shape memory effect, excellent biocompatibility,

non-toxicity, bio-degradability and drug permeability, we chose

cPCL as the drug carrier[15,16]. Then, considering the long degra-

dation time of cPCL (more than 14 months) we added PSA to adjust

its degradation rate. PSA can be used as controlled release devices

for short-lived drugs by the surface erosion phenomenon and con-

sequently provides a sustained release effect for the drug over an

extended period of time. Furthermore, the degradation rate of

PSA can be well adjusted by changing its molecular weight

[17,18]. Because of the above excellent properties, we believe

PSA could become a good reinforcement to lower the cPCLs degra-

dation time and the device based on biodegradable polymer can

degrade after a defined time period, thus eliminating the need

for a second surgery for removal.

On the other hand, SMP were rapidly developed in biomedical

fields for their potential applications in recent years, including

the seam of the minimally invasive surgery, the stent of bone

and tissue repair[1,14,15]. Unfortunately, some side effects could

be observed after these surgeries or repairs [16,19]. The common

solution to this problem was to take medicine by oral or injection,

which turns out not effective enough [20]. In order to fulfill the

complex demands as medical devices during biomaterials-assisted

therapies, the biomaterials with several functions such as shape

memory effect and controlled drug release have been realized

[7]. Considering this situation, we have pulled toward a better

way to design a drug-loaded shape memory polymer. We expected

that it has excellent shape memory property, whats more impor-

tant is that through sustained release, the loaded drug can resist lo-

cal inflammation. In summary, the shape memory effect enables

the minimally invasive implantation of bulky devices. The function

of controlled drug release can be used to treat infections and re-

duce inflammatory response.

In this study, a series of cPCL/PSA composites were prepared in

order to colligate their own advantages and overcome their draw-

backs. Then, the drug paracetamol was incorporated in the com-

posites to investigate its drug delivery properties. We prepared

three kinds of samples: cPCL, paracetamol-loaded cPCL and

1359-8368/$ - see front matter 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.compositesb.2010.07.001

* Corresponding author. Tel.: +86 28 87634023; fax: +86 28 87634649.

E-mail addresses: [email protected],[email protected](S. Zhou).

Composites: Part B 41 (2010) 537542

Contents lists available at ScienceDirect

Composites: Part B

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c o m p o s i t e s b
http://dx.doi.org/10.1016/j.compositesb.2010.07.001mailto:[email protected]:[email protected]:[email protected]://dx.doi.org/10.1016/j.compositesb.2010.07.001http://www.sciencedirect.com/science/journal/13598368http://www.elsevier.com/locate/compositesbhttp://www.elsevier.com/locate/compositesbhttp://www.sciencedirect.com/science/journal/13598368http://dx.doi.org/10.1016/j.compositesb.2010.07.001mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.compositesb.2010.07.001


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paracetamol-loaded cPCL/PSA composites, and further investigated

their properties, including shape memory effect, mechanical per-

formance and in vitro bio-degradability.

2. Materials and methods

2.1. Materials

Linear PCL was synthesized in our lab as the previous report

[21]. The molecular weight (Mw) determined by gel permeation

chromatograph (GPC) is 112,000. Benzoyl peroxide (BPO) was pur-

chased from Chengdu Kelong Chemical Reagent Company (Sichu-

an, Chengdu, China). PSA (Mw: 20,000) was polymerized by a

melt polycondensation process without adding any catalyst in

our lab. Paracetamol was obtained from Kangquan Pharmaceuti-

cals Inc., China. All the other chemicals and solvents were of re-

agent grade or better.

2.2. Preparing of cPCL, paracetamol-loaded cPCL and cPCL/PSA

composites

Pre-weighted linear PCL with 1.5 wt.% BPO (BPO as the cross-linking agent)[22]was dissolved in CH2Cl2under stirring, and or-

ganic solvent was volatilized by stirring and then dried under

vacuum. Later, these completely dried composites were press-

molded at 135C for 10 min in a mold (because BPO enable cross-

linking reaction to occur at 130C [22]. As a result, the required

slices made up of cPCL with thickness of about 0.2 mm were

obtained.

Paracetamol (5.0 wt.%) was dissolved in 5 mL acetone, and the

solution was transferred to 20 mL CH2Cl2 under stirring. Then,

2 h later after cPCL was immersed in mixed solution, paraceta-

mol-loaded cPCL gel (cPCL/drug) was obtained due to paracetamol

solution penetrating into its cross-linking structure. Finally, the re-

sulted cPCL gel was dried by volatilizing.

We can derive the paracetamol-loaded cPCL/PSA composite(cPCL/PSA/drug) in a similar way as above. The only difference

was in the first stage linear PCL as well as 1.5 wt.% BPO and

5.0 wt.% PSA were dissolved in CH2Cl2 under stirring with the fol-

lowing steps the same as the fabrication of cPCL. Paracetamol-

loaded cPCL/PSA composite with thickness of about 0.2 mm can

be fabricated, which was prepared as mentioned above.

2.3. Characterization

Nicolet 5700 Fourier Transform Infrared Spectroscopy (FT-IR,

Thermo Electron, USA) was performed to identify the changes of

some functional groups. All specimens were made into particles

and mixed with KBr grains at a weight ratio of 0.51%. Pure KBr

was used as IR spectral reference and each sample was recordedfrom 4000 to 400 cm1 by 64 scans.

Static tensile test was accomplished at the crosshead speed of

5 mm/min at room temperature using a universal testing machine

Instron 5567, Instron Co., Massachusetts. Prior to the test the spec-

imens should be of dumbbell shape cut from pressed composites.

Of all the mechanical properties, Youngs modulus E and tensile

strengthrb were tested.

Dynamic mechanical analysis (DMA) was carried out on a

DMA983 analyzer (Du Pont, USA), using a tensile resonant mode

at a heating rate of 5 C/min from 30 to 90 C and at a frequency

of 1 Hz. The storage modulus E0 for specimen size

50 10 2 mm (length width thickness) was tested.

Gel fraction estimate can be done by the following method: all

the pre-weighted specimens,m0, are subjected to swell in CHCl3inan attempt to gather gel, which needs 24 h to insure steady gel

fraction values, and then a high speed centrifuge was employed

to detach gel from sol. During the process, an observable phenom-

enon may be noted that some agglomerate of gel floats on the sur-

face of transparent gel solution in the centrifuge tube. Afterward a

dried gel mass, m1 is noted, the gel fraction can be calculated as

follows:

Gel fraction % m1m0 100%:

In vitro degradation of all samples was carried out as follows.

Pre-weighed samples were placed individually in test tubes con-

taining 10 mL of 0.1 M phosphate buffered saline (PBS) at pH 7.4.

The tubes were kept in a thermo-stated incubator (Haerbin Dong-

ming Medical Equipment Company) which was maintained at

37C and 107 cycles per minute. The degradation process was

evaluated from the weight loss, the pH change, the gel fraction,

shape memory properties and mechanical properties at predeter-

mined intervals.

In vitro drug release was carried out as follows. Predetermined

samples were suspended in a test tube containing PBS with pH 7.4.

The test tubes were placed in a same incubator and continuously

agitated with the same condition as mentioned above. At predeter-

mined intervals, 1.0 mL of supernatant was collected and 1.0 mL of

fresh PBS was added to the test tube. Amount of released paracet-

amol was determined with an UVvisible spectrumphotometer at

absorbance of 247 nm.

3. Results and discussions

3.1. Characteristic analysis

Fig. 1 shows FT-IR images of cPCL, paracetamol and paraceta-

mol-loaded cPCL. In view of strong oxidizing property of BPO and

weak reducibility of paracetamol, the drug may be oxidized if these

two substances meet together[23,24]. Therefore, during our exper-

iment the drug was added into polymer matrix after the crosslink-

ing process was finished in order to avoid the pollution. FT-IR testwas used to inspect whether the added paracetamol was oxidized

by BPO. From Fig. 1a, wecan see that the IR absorption peaks of par-

acetamol mainly consist of the NH groups characteristic spectral

line at 3325 cm1, the C@O flex vibrate characteristic spectral line

at 1653 cm1, and phenyl-hydroxyl characteristic spectral line at

1245 cm1. InFig. 1b, we can observe that the IR absorption peaks

of cPCL mainly consist of carbonyl characteristic spectral line at

1171 cm1, ester functional groups at 1722 cm1 and methylene

at 2935 cm1. As shown in Fig. 1c, we could find the FT-IR bands

Fig. 1. The FT-IR spectrum of (a) paracetamol drug, (b) cPCL, and (c) cPCL/paracetamol.

538 Y. Xiao et al./ Composites: Part B 41 (2010) 537542


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of paracetamol took a slight 1red-shift and comparatively the bands

of cPCL took blue-shift. This result indicated that there is a small

interaction between cPCL matrix and paracetamol. According to some

previous literatures, we speculate this interaction is the hydrogen

bonding which attributed by the OH from the paracetamol and

the C@O from the cPCL[25]. However, from the curves ofFig. 1ac,

we could observe that this red or blue-shift is too small and cannot

make great influence to the structure of paracetamol and cPCL. On

the other hand, from the Fig. 1c, we could not find distinct C@C bands

of quinone which was generated by the oxidized hydroxybenzene at

1690 cm1. So, we could draw a conclusion that the paracetamol is

not polluted during the crosslinking process.

3.2. Mechanical and shape memory properties tests

Table 1shows the mechanical properties of cPCL, cPCL/drug and

cPCL/PSA/drug samples. From this table, we can definitely find that

the pure cPCL possess the best mechanical properties. With drug or

PSA added into cPCL matrix, the mechanical properties such as

elasticity modulus, yields strength, broken strength and elongation

at break decreased gradually. The reason mainly could be summa-

rized as follows: There will be a few lacunas such as cracks, hol-

lows after the addition of PSA or drug. Those lacunas could

largely decrease the interfacial tension [26]. On the other hand,

the addition PSA may bring a phase separation between PSA mol-

ecules and cPCLs crosslinked structure. Noteworthily, according tothe report by Wu et al. the basic requirement of mechanical prop-

erties for biomedical application is relatively low[27]. Therefore,

although the accession PSA or drugs to polymer matrix led poorer

mechanical properties, it could not distinctly influence the applica-

tion of the materials in biomedical field.

Table 2summarizes the recovery ratio and gel fraction of cPCL,

cPCL/drug and cPCL/PSA/drug. From this table, the shape recovery

ratio of the three samples is nearly similar. The results illuminate

that the added PSA and drug have almost no impact to the shape

memory properties. Simultaneously, the measure of gel fraction

is carried out to reflect the crosslinking degree of these composites

and the relationship between the crosslinking degree and the

shape memory properties. As reported by a few researchers, the

gel content has a close contact to the crosslinking degree andmoreover, the crosslinking degree is the main factor to influence

the shape memory properties of polymer [28,29]. Therefore, to

investigate the relationships between shape memory property

and the gel content is necessary. Our previous report indicated that

the shape memory property of cPCL was mainly dependent on its

crosslinking degree, or in other words, dependent on the BPO con-

tent[28]. It can be explained that crosslinking process will produce

the crosslinked points acted as the fixed phase for shape memory

in the PCL matrix. Therefore, the shape memory properties were

naturally enhanced with the increasing of the fixed phase[29]. Fur-

thermore, cPCL with higher crosslinked degree held more cross-

linking structures, i.e. chemical crosslinked network, which can

store more elastic deformation energy. Thus, the nearly same gel

fraction also determines the close recovery ratio of the three sam-

ples. In addition, the reversible strain of cPCL decreased with

increasing gel content. So we can conclude that the more gel con-

tent in polymer matrix, the better shape memory properties could

be obtained.

Fig. 2 shows the change of storage modulus (E0) among pure

cPCL, cPCL/drug, cPCL/PSA/drug from DMA behavior. All the three

specimens have a phase-transition temperature range of about

40C where E0 suddenly decreases with the increasing tempera-

ture. This is necessary for shape memory polymers. The peak of

modulus curve is often employed to define the glass transition

temperature (Tg)[26], but in our test, the decrease of the E0 is cor-responding to the melting temperature (Tm) area of PCL. Therefore,

our DMA results illustrate that the storage modulus of the speci-

mens is almost constant at a temperature area of the ordinary

state. For example,Tmfor the cPCL is about 55.5 C[16], the storage

modulus is almost constant below 35 C (Tm 20C) at 330 MPa

and we also can observe a lower modulus plain emerges where

about 0.7 MPa at 80C (Tm +20C). As reported by Zhou et al. the

storage modulus of their composites at 22.8 C (E0 = 3220 MPa) is

about two orders of magnitude larger than that at 82.8C

(E= 29.6 MPa)[26]. Thus, we could find great shape memory prop-

erties from their composites (the recovery ratio is nearly 95%). A

fall up to three orders of magnitude can be obtained in our DMA

images. Hence, these composites can provide novel shape memory

properties.To approve the great shape memory properties of our samples,

we also took a series of photos with digital camera to show the

specimens shape recovery progress. As shown in Fig. 3, the initial

shape of our materials was made to a strip (the angle was 180),

and then these two strips were completely fold up (the angle

was 0). After that, the deformed samples were heated and started

Table 1

Mechanical properties of cPCL, cPCL/paracetamol and cPCL/PSA/paracetamol samples.

Samples E(MPa) ds (MPa) db (MPa) Le (%)

cPCL 411 20.6 18.84 2.61 20.12 2.38 800 54.3

cPCL/ dr ug 3 98 3 8.7 1 5.0 5 1 .3 2 1 7.0 5 1 .5 9 6 57 3 6.8

cPCL/PSA/drug 280 35.9 11.04 1.36 13.20 2.21 402 40.1

E: modulus of elasticity; ds: yield strength; db: tensile strength; L e: elongation at

break.

Table 2

Shape memory properties of cPCL, cPCL/paracetamol and cPCL/PSA/paracetamol

samples.

Samples Recovery ratio (%) Gel fraction (%)

cPCL 95.6 1.05 42.8 0.95

cPCL/drug 94.5 0.92 45.2 0.99

cPCL/PSA/drug 95.2 1.07 39.6 0.89

Fig. 2. Storage modulus vs. temperature of cPCL, cPCL/paracetamol and cPCL/PSA/paracetamol by DMA.

1 For interpretation of color in Figs. 16, the reader is referred to the web version ofthis article.

Y. Xiao et al./ Composites: Part B 41 (2010) 537542 539


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to recover immediately. The samples were recovered to their half

shape (the angle was 90) at 15 s and recovered basically to the ori-

ginal shape only at 30 s. The results indicated that our composites

had excellent shape memory properties.

3.3. In vitro degradation and drug release test

From theFig. 4we can observe that the addition of PSA indeed

speeded up the biodegradation of cPCL.Fig. 4a shows the weightloss of the three samples vs. degradation time, and we can clearly

see that the weight of pristine cPCL decreases quite smoothly, and

changes a little on the whole, and the other two samples possess a

quick-drop process in the first 2 weeks. This is because the lacunas

engendered from the paracetamol introduced into cPCL can im-

prove water penetrating into polymer matrix, which results in a

faster degradation of cPCL. Furthermore, compared to the cPCL/

drug sample, the weight of cPCL/PSA/drug decreased much faster.

It means that the addition of PSA will further speed up the biodeg-

radation of cPCL. The reason may be analyzed from two aspects

that PSA can accelerate the degradation rate of cPCL matrix. One

is that the phase separation between PSA and cPCL could increase

water penetrating into cPCL matrix, the other is as a result of the

acidity of the degradation products of PSA. The nature of cPCL deg-

radation is the hydrolysis of ester bonds in cPCL chains. It is well

known that the hydrolysis can be triggered by water and catalyzed

by the acidic medium.Fig. 4b displays the media pH decrease vs.

degradation time. The result is almost consistent withFig. 4a.

To evaluate the effect of polymer degradation on its shape mem-

ory property, we investigated the change of recovery ratio and gel

content vs. degradation time. As shown inFig. 4c and d, the trend

Fig. 3. The photo showing the shape memory recovery process of (a) cPCL/paracetamol and (b) cPCL/PSA/paracetamol.

Fig. 4. Biodegradation properties vs. biodegradation time of cPCL, cPCL/paracetamol and cPCL/PSA/paracetamol: (a) loss weight, (b) pH, (c) recovery ratio and (d) gel content.



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profiles almost correspond to theFig.4a and b.We can see thatwith

the decrease of gel content the samples shape recovery ratio got an

obvious fall, too. This phenomenon is similar to some previous re-

ports and the reason can be described as follows: the inner cross-

linked structure of the cPCL is impaired companying with the

degradation process, and the number of the crosslinked point,

namely the shape memory fixed phase decreased [29]. It also can

beprovedby the gel content asshown inFig.4d. Along with the bio-degradation experiment, the gel content of these three samples de-

creases, which inevitably leads to recede the shape memory

properties.Perhaps a better questionnow is whythere is no recovery

ratio data of cPCL/PSA/drug after 6 weeks. This is because 6 weeks

degradation makes these kinds of samples more and more brittle,

the material would be broken immediately if we changed the sam-

ples shape,so wecannot getthe properdata in thefollowing period.

The mechanical properties must be changed due to the high

molecular weight polymer degradation into low molecular weight

polymer. So we estimated the degradation behaviors by testing the

mechanical strength of samples.Fig. 5shows the mechanical prop-

erties of the three samples, including elasticity modulus and ten-

sile strength. The results and the reasons are similar as we got in

Fig. 4. Here, we need to emphasize the phenomenon of the biodeg-

radation test. For the pristine cPCL, in shape these samples have al-

most no changes after 14 weeks biodegradation except a little

white floccus can be found in the biodegradation medium. For

the cPCL/drug samples, some apertures appear on their surface

with the degradation time increasing, and the changes of the sam-

ples shape became more obvious, and the white floccus in the

medium was much more than that of pristine cPCL. For the last

samples, the shape kept well, but the material got quite brittle.The reason is that the added PSA improves the biodegradation rate

of the cPCL.

Fig. 6 shows the drug release profiles of cPCL/PSA/drug and

cPCL/drug samples. From this image, we can see that initial burst

effect happened during the first 4 days, and within the period

nearly 45% paracetamol was released, however, the value has

plummeted to only 15% during the following 16 days. It is well

known that drug release from biodegradable polymer is mainly

due to polymer degradation. So here the release result is in accord

with our conclusions fromFigs. 4 and 5. In the other words, the

addition of PSA accelerating the polymer matrix degradation re-

sulted in a faster drug release.

4. Conclusions

In this paper, we successfully prepared three kinds of samples

combining biodegradation, controlled drug release and shape

memory effect by a simple method. All the drug-loaded samples

have satisfactory shape memory properties, mechanical properties

and drug release behavior. The degradation rate of the PCL/PSA/

drug is significantly faster than the other two samples, and simul-

taneously leads a faster drug release, which means that the intro-

ducing of PSA into cPCL matrix can adjust its degradation. Although

the addition of PSA and drug will depress cPCLs mechanical prop-

erty, it has little influence on its shape memory effect, and thus it

could not bring an adverse impact on its biomedical application. In

a word, the multifunctional polymer composite has great potential

in minimally invasive surgery such as drug eluting stents in bio-

medical field.

Acknowledgements

This work was partially supported by National Natural Science

Foundation of China (50773065, 30970723), Programs for New

Century Excellent Talents in university, Ministry of Education of

China (NCET-07-0719) and Sichuan Prominent Young Talent Pro-

gram (08ZQ026-040).

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