ORI GIN AL PA PER

On the effect of macromolecular composition and drugloading on thermal and tensile mechanical propertiesof methyl methacrylate and butyl methacrylatecopolymers

Mariacristina Gagliardi

Received: 29 May 2013 / Revised: 26 September 2013 / Accepted: 7 November 2013 /

Published online: 14 November 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract In the last years, drug-eluting stents (DES) were considered as an

important biomedical technology for cardiovascular intervention. In these devices, a

thin polymer coating covers the metallic structure, aiming at the release of one or

more active principles with controlled delivery kinetics. During DES implantation,

structural failures on the thin coating may occur because of the mechanical

expansion of the structure. The presence of a drug in the polymer matrix could

severely influence mechanical properties, thus a mechanical characterisation of

polymers and drug-loaded matrices results fundamental. To characterise a material

produced for the manufacturing of drug-loaded coatings for DES, in the present

work the thermomechanical analysis of an acrylic copolymer loaded with a drug is

proposed. Obtained results showed that macromolecular composition could be

varied to obtain the desired mechanical compliance; in addition, the drug can act as

plasticiser. The present study would underline that it is possible to control

mechanical properties by synthesising a tailored copolymer; furthermore, the

importance of the study of the final system is fundamental when a polymer is

considered as potential candidate to obtain coatings for DES.

Keywords Coatings � Thermal properties � Mechanical properties �Drug eluting stents � Poly(methylmethacrylate-co-butylmethacrylate)

M. Gagliardi

Department of Chemical Engineering, Industrial Chemistry and Materials Science,

University of Pisa, Largo Lucio Lazzarino, 56126 Pisa, Italy

Present Address:

M. Gagliardi (&)

Center for Micro-BioRobotics @SSSA, Istituto Italiano di Tecnologia, Viale Rinaldo Piaggio,

34, 56025 Pontedera, PI, Italy

e-mail: mariacristina.gagliardi@iit.it

123

Polym. Bull. (2014) 71:533–544

DOI 10.1007/s00289-013-1075-0

Introduction

Drug-eluting stents (DES) are small-slotted devices generally coated with a thin

polymeric layer loaded with one or more active principles [1]. These devices are

used in the treatment of coronary artery diseases and are implanted via balloon

angioplasty, an intravascular procedure based on the use of a catheter, equipped by a

balloon that is inflated to expand the stent in the site of the pathology, restoring the

perviety of the blood vessel. The presence of drugs in the coating is requested to

prevent the restenosis post-stenting [2], caused by a negative response to the

intervention. When released from the coating, therapeutic agents are directly at the

target site, increasing the pharmacological potential of the treatment [3–5]. The use

of a polymer to coat the metallic device causes several problems related to the

haemo- and cyto-compatibility [6, 7], the potential release of products of the

degradation of the coatings [8, 9] and the possibility of cracking or delamination

during the stent deployment and implantation [10–12], thus a tight control of the

drug delivery kinetics resulted fundamental [13, 14] to justify the introduction of the

polymeric component in a complex system such as a coronary stent. Concerning the

integrity of the coating, several studies are reported in literature [10–12, 15, 16],

concluding that a complete analysis of the mechanical properties of the final drug-

loaded system is important to prevent the cracking of the coating. During the

implant of a stent, a plastic deformation of the metallic structure is performed and

the diameter of the device is increased by 200–300 % in respect to the starting

diameter. If the coating covers the whole structure, there are several zones of the

device where high deformations occur. Then, a good material to obtain coatings for

drug eluting stents has to be soft and highly ductile; also, it has to show high

toughness to absorb a greater amount of energy before reaching the rupture. The

presence of active principles cannot be neglected in the mechanical characterisation

of the material, considering that the drug molecules could interact with the

polymeric chains. Interactions are affected by the chemical composition of both

polymeric matrix and drug and, basing on their differences, adhesion between

molecules could be different by varying the polymeric platform and the active

principle. Some recent studies reported the analysis of mechanical properties of

polymer matrices loaded with drugs [17, 18], underlining that a significant variation

may occur in the presence of both plasticisers and anti-plasticisers, also by varying

their concentration in the polymer matrix.

Among the large number of polymers suitable to obtain controlled delivery

kinetics, polymethylmethacrylate (PMMA) is a good candidate able to furnish a

prolonged drug release over time. It is an interesting characteristic for a drug-eluting

polymer platform for DES because the pharmacological treatment may be necessary

for several months after implantation [19, 20]. On the other hand, PMMA is a stiff

and low ductile polymer and it could lead to coating ruptures during production

processes and stent implantation. Another interesting polymer is polybutylmethac-

rylate (PBMA) that is already used in a FDA-approved DES (Cypher stent, Johnson

and Johnson) [21] thanks to its adhesive properties; in addition, literature reports

that its copolymers show interesting properties for other different biomedical

applications, such as in drug delivery systems [22] and biosensors [23]. Considering

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123

that drug delivery kinetics of PMMA and PBMA was found to be significantly

different [24], it is reasonable to consider a copolymer of methylmethacrylate and

butylmethacrylate to tune this characteristic. However, drug release kinetics cannot

be considered as the most important characteristic of a DES coating. Other different

properties have to be analysed, such as biocompatibility and drug release efficacy on

cells [25], but also the possibility to realise a coating and the mechanical strength of

the final product. In the present work, the mechanical analysis of a copolymer

synthesised using methyl methacrylate (MMA) and butyl methacrylate (BMA) in

three different macromolecular compositions is reported, evaluating in the first part

of the work the effect of the macromolecular composition on mechanical properties.

Then, the analysis of drug-loaded specimens is reported to evaluate how the

presence of the drug affects the mechanical behaviour of the materials. In the last

part of the work, the prediction of the Young’s modulus, as a function of

macromolecular composition and drug loading, using mathematical models is

reported and an empirical model was developed for this aim.

Materials and methods

Polymeric materials used in the present work were poly(methyl methacrylate),

poly(butyl methacrylate) and three of their copolymers poly(methyl methacrylate-

co-butyl methacrylate) [P(MMA-co-BMA)]. Materials were synthesised as

described in a previous work [26]. In Table 1, the composition of the starting

monomer mixture used to synthesise copolymers and the final macromolecular

composition, together with the nomenclature that will be used in this work to

identify the materials, is reported. Folic acid (FA, Sigma�) was used as drug model.

Three different percentage of loading ratios were selected: 1, 5 and 10 % w/w in

respect to the polymer.

Preparation of dog-bone samples

Samples not containing the drug were prepared by casting from polymeric solutions

in tetrahydrofuran (THF, Carlo Erba Reagenti). Polymeric solutions with concen-

tration of 2 % w/v of polymer were prepared. When polymeric powders were

completely dissolved, solutions were poured onto silicon moulds to obtain dog-bone

Table 1 Poly(methyl methacrylate-co-butyl methacrylate) copolymer percentage compositions and

nomenclature that will be used in the present work

Nomenclature % molar composition

in the starting reaction

recipe (MMA/BMA)

Final % molar

composition

(MMA/BMA)

Final % weight

composition

(MMA/BMA)

P(MMA-co-BMA) 87.5/12.5 87.5/12.5 86.9/13.1 82.4/17.6

P(MMA-co-BMA) 75/25 75/25 74.3/25.7 67.1/32.9

P(MMA-co-BMA) 50/50 50/50 50.8/49.2 42.1/57.9

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samples. 4 ml of solution was poured in each mould to obtain one specimen. The

casting procedure was carried out in a vented oven maintained at 40 ± 1 �C for 5 h.

In Fig. 1, the mould used and dimensions of obtained samples are reported. Drug-

loaded samples were prepared with the same technique used to obtain not-loaded

samples, changing the starting solution. In this case, the starting solution was

prepared dissolving a blend of polymeric powder and FA in THF. The amount of

polymer was maintained fixed (2 % w/v), while three different amounts of FA were

considered: 1, 5 and 10 % in weight of drug in respect to the polymer weight. Five

specimens were tested for each system and the results following reported represent

the mean value of these tests. The thicknesses of obtained samples are reported in

Table 2.

Thermal and tensile mechanical characterisation

Glass transition temperatures (Tg) for synthesised copolymers were evaluated by

differential scanning calorimetry (DSC). Calorimetric analyses were carried out

using a Perkin Elmer DSC 7 instrument. Five film-shaped samples (6.3 ± 1.2 mg)

for each polymeric system were analysed. The thermal behaviour of the materials

was followed from 0 to 200 �C (heating and cooling) at a rate of 10 �C/min under

N2 flux (10 mL/min). Results obtained from the second heating scan were

considered to evaluate the Tg.

Fig. 1 a Silicon mould used to prepare dog-bone samples and b geometric characteristics of obtainedsamples

Table 2 Thicknesses of specimens (lm) obtained using the dog-bone mould by varying the percentage

amount (w/w) of folic acid loaded in the starting solution

Material FA 0 % FA 1 % FA 5 % FA 10 %

PMMA 15.2 ± 3.2 20.4 ± 5.6 13.6 ± 4.4 19.6 ± 6.4

P(MMA-co-BMA) 87.5/12.5 16.2 ± 3.2 25.6 ± 5.6 30.2 ± 2.8 30.4 ± 2.6

P(MMA-co-BMA) 75/25 19.4 ± 6.4 20.4 ± 0.6 23.4 ± 4.6 26.0 ± 4.0

P(MMA-co-BMA) 50/50 14.0 ± 4.0 16.6 ± 3.4 13.0 ± 3.0 15.4 ± 4.6

PBMA 12.8 ± 0.8 15.8 ± 7.2 19.6 ± 8.4 12.8 ± 3.2

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Tensile strength tests were performed using the isotonic transducers Ugo Basile

Biological Research Apparatus. Load applied was ramped from 0 to 5 N in 3 h

(loading rate: 0.028 N/min). Tests were performed at controlled room temperature

(22 �C).

Results and discussion

In Fig. 2, values of Tg obtained for analysed samples are reported for each

polymeric platform by varying the amount of FA loaded into systems. It was

possible to underline two different plasticising effects arising by increasing: (1) the

BMA units into the copolymeric chains and (2) the amount of FA loaded into

systems. The first effect can be directly related to the presence of the lateral

substituents that are more flexible for BMA units than MMA. n-butyl substituents,

in fact, can entangle nearby polymer chains, causing a decrease of the glass

transition temperature [26]. Considering the effect of FA loading, a slight decrease

of the Tg was registered for each system with the increase of the solute loading. The

decrease of the Tg could be directly related to a plasticiser effect of FA molecules

[27]. In fact, after the addition of FA, solute molecules come between polymer

chains, pushing them apart from each other. The presence of solute molecules into

the macromolecular spaces causes an increase of the free volume, thus polymer

macromolecules can more easily slide past each other. As a final result, polymer

chains can move around at a lower temperature than pure polymer, consequently a

lower Tg can be recorded.

Figure 3a shows the uniaxial stretching response exhibited by the different

P(MMA-co-BMA) copolymers compared to homopolymers. Mechanical properties

were found to be strongly dependent on the macromolecular composition (Table 3).

In particular, in respect to r-e curves of PMMA and PBMA, copolymers showed

intermediate properties. The shape of the stress–strain curve gradually was modified

by increasing the BMA amount in the molecular composition and ductility increased

Fig. 2 Glass transition temperatures (Tg) evaluated for pure materials and FA-loaded specimens byvarying the amount of solute introduced in polymeric matrices; error bars (reported) were found to beB1.0 % for each measurement

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gradually by increasing the BMA amount, while the ultimate stress decreased. In

fact, in copolymers 87.5/12.5 and 75/25, containing a low BMA amount, a

homogeneous deformation with a negligible plastic region was observed; while in

the copolymer 50/50, the plastic region become more evident, showing a behaviour

more similar to PBMA. In particular, PMMA showed to be fragile and the rupture

occurred without plastic effects and the same behaviour occurred in the analysis of

the copolymer 87.5/12.5. On the contrary, increasing the BMA amount a plastic

deformation occurred and the plastic strain increased gradually with the increase in

BMA content. According to these observations, Young’s modulus (E), first yield

stress (r0,ys) and strength at break (ru) increased with the increase in MMA fraction

while deformation at break (eu) decreased with this parameter, due to the greater

stiffness introduced in the materials by the MMA units. Another important

mechanical parameter is the toughness. This parameter can be defined as an

indication of the energy that a material can absorb before the breaking occurrence

and it could be evaluated as the area under the r–e curve. Obtained values are

reported in Fig. 3b. Also in this case, a correlation between this mechanical

parameter and the macromolecular composition can be highlighted; increasing the

BMA amount toughness increased rapidly for low BMA amount, but a smaller

difference between copolymer 75/25 and 50/50 was found.

Figure 3c reports as example the uniaxial stretching response exhibited by the

copolymer P(MMA-co-BMA) 87.5/12.5 by varying the FA loading. Other materials

showed a similar trend, with a decrease of the Young’s modulus, the first yield

stress, the strength at break and an increase in the deformation at break. Numerical

Fig. 3 Mechanical parameters in function of the actual BMA molar fraction in the macromolecularcomposition: a r–e curves obtained from tensile tests (one single experiment); b toughness of thematerials, evaluated measuring the area under the r–e curve. Mechanical parameters in function of the FAloading: c r–e curves obtained from tensile tests (one single experiment) copolymer 87.5/12.5;d toughness of the materials

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data are summarised in Table 4. Considering the effect of the percentage FA

loading, the overall highlighted trend was the same registered for copolymer 87.5/

12.5. Concerning the energy at break (Fig. 3d), also in this case toughness increased

with the increase in BMA amount and decreased with the increase in FA fraction.

Even if a trend of mechanical properties by varying the amount of drug loaded was

underlined, a comparison of obtained data showed that the plasticizer effect of the

drug did not significantly increase with concentration. It may be due to the solubility

of the drug in the polymeric matrices, higher than the amount of drug loaded; the

good solubility led to a homogeneous distribution of FA, thus interactions between

polymer molecules decreased, because of the increase of the free volume caused by

the presence of FA, but not significantly.

Mathematical modelling of Young’s modulus

The effect of macromolecular composition on the elastic modulus of copolymers

was evaluated using two different equations:

1

E¼ x1

E1

þ 1� x1

E2

ð1Þ

Where x1 is the weight fraction of the component 1, while E1 and E2 are the elastic

modulus of the component 1 and 2 (homopolymers), respectively.

E ¼ x1 � E1 þ c � ð1� x1Þ � E2

x1 þ c � ð1� x1Þð2Þ

where c is a fitting parameter obtained by the plot of ðE � E1Þ vs. ðE2 � EÞ � 1�x1

x1.

For the proposed system, c was found to be 0.519. Obtained results found with cited

models are reported in Fig. 4. Equations used to predict the Young’s modulus were

derived from two models generally used in the prediction of the thermal behaviour

of copolymers, in particular from Fox (Eq. 1) and Gordon–Taylor (Eq. 2) models

[28]. Models seem to fit well also with mechanical properties and it allowed hy-

pothesising that both equations could be extended also to the prediction of Young’s

modulus of copolymers.

Table 3 Young’s modulus E (MPa), first yield stress r0,ys (MPa), strength at break ru (MPa) and

deformation at break eu evaluated through tensile tests; mean values were evaluated from five experi-

mental tests; r0,ys was identified as the last point of the linear region showing a correlation between

experimental data and linear curve fitting [0.97

Material E (MPa) r0,ys (MPa) ru (MPa) eu

PMMA 780 ± 8 48 ± 4 70 ± 6 0.06 ± 0.01

P(MMA-co-BMA) 87.5/12.5 580 ± 6 44 ± 4 65 ± 8 0.08 ± 0.02

P(MMA-co-BMA) 75/25 476 ± 7 29 ± 3 53 ± 9 0.14 ± 0.03

P(MMA-co-BMA) 50/50 351 ± 9 19 ± 5 38 ± 5 0.18 ± 0.02

PBMA 130 ± 8 14 ± 3 27 ± 5 0.38 ± 0.03

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Table 4 Young’s modulus E (MPa), first yield stress r0,ys (MPa), strength at break ru (MPa) and

deformation at break eu evaluated through tensile tests on specimens by varying the percentage FA

loading; mean values were evaluated from five experimental tests

Material FA loading

1 % 5 % 10 %

Young’s modulus E (MPa)

PMMA 531 ± 19 476 ± 13 402 ± 18

P(MMA-co-BMA) 87.5/12.5 327 ± 11 236 ± 12 225 ± 16

P(MMA-co-BMA) 75/25 242 ± 12 228 ± 11 181 ± 12

P(MMA-co-BMA) 50/50 160 ± 10 123 ± 8 118 ± 9

PBMA 70 ± 6 46 ± 5 33 ± 8

First yield stress r0,ys (MPa)

PMMA 19 ± 6 16 ± 4 13 ± 1

P(MMA-co-BMA) 87.5/12.5 15 ± 3 14 ± 2 12 ± 3

P(MMA-co-BMA) 75/25 10 ± 4 7 ± 4 4 ± 2

P(MMA-co-BMA) 50/50 5 ± 2 3 ± 2 2 ± 1

PBMA 5 ± 3 2 ± 1 2 ± 1

Strength at break ru (MPa)

PMMA 35 ± 8 34 ± 6 31 ± 7

P(MMA-co-BMA) 87.5/12.5 34 ± 6 33 ± 4 29 ± 5

P(MMA-co-BMA) 75/25 31 ± 2 28 ± 8 27 ± 3

P(MMA-co-BMA) 50/50 23 ± 4 15 ± 4 14 ± 5

PBMA 19 ± 1 14 ± 3 13 ± 3

Deformation at break eu

PMMA 0.07 ± 0.02 0.08 ± 0.01 0.09 ± 0.01

P(MMA-co-BMA) 87.5/12.5 0.08 ± 0.02 0.09 ± 0.01 0.12 ± 0.02

P(MMA-co-BMA) 75/25 0.15 ± 0.02 0.16 ± 0.03 0.18 ± 0.01

P(MMA-co-BMA) 50/50 0.20 ± 0.03 0.22 ± 0.02 0.40 ± 0.03

PBMA 0.39 ± 0.01 0.41 ± 0.01 0.45 ± 0.02

Fig. 4 Theoretical models used for the prediction of Young’s modulus by varying the macromolecularcomposition; correlations between experimental data and mathematical models were found to be 0.965and 0.997 for models described by Eqs. (1) and (2), respectively

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To predict the effect of FA loading, six different mathematical models already

described in literature [29] were used. Studied models are summarised in Table 5.

Reported equations describe the prediction of the Young’s modulus of polymeric

Table 5 Mathematical models used to describe the Young’s modulus by varying the volume fraction of

filler; u is the volume fraction of the filler

Model Equation Conditions

Einstein E ¼ Em � ð1þ 2:5 � uÞ Perfect adhesion

filler/matrixGuth-Smallwood E ¼ Em � ð1þ 2:5 � uþ 14:1 � u2ÞSlip condition E ¼ Em � ð1þ uÞ Polymer matrix slips

by filler particles

Sato-Furukawa E ¼ Em � 1þ u2=3

2�ð1�u1=3Þ

� �� 1þ w � fð Þ � u2=3�w�f

1�u1=3ð Þ�u

h iPoor adhesion

filler/matrix

where w ¼ u3

� �� 1þu1=3�u2=3

1�u1=3þu2=3 and 0 B f B 1

Series/parallel E ¼ Em � um and E ¼ Em

umrespectively

Fig. 5 Theoretical models used for the prediction of Young’s modulus: a Einstein; b Guth-Smallwood;c slip condition; d Sato Furukawa; e series/parallel; reported plots referred to polymeric systems loadedwith 1 % of FA

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matrices loaded with a plasticiser composed of rigid fillers. In the present work,

copolymers were loaded with an active principle and previously reported models

were unreliable for this aim. In Fig. 5, obtained results for copolymers loaded with

1 % of FA are reported, for other drug loadings results were similar and were not

reported. Thus, a novel empirical model was developed, expressed by Eq. (3):

E ¼ k � Em � ð1� uÞ½ � 1þ2=3ð Þ ð3Þ

Where k is a fitting parameter and value from experimental data was found to be

0.825 ± 0.003 for all systems, by varying both macromolecular composition and

drug loading. Proposed model resulted in good agreement with experimental data

(Fig. 6). However, this model did not expressly take the polymer/drug adhesion into

account. It is reasonable to consider that this characteristic only affected the value of

k because no significant differences between different drug loadings were found. For

this reason, the value of k may significantly vary if other polymer/drug systems are

considered.

Conclusion

In the present work, the effect of macromolecular composition and drug loading on

thermomechanical properties of acrylic copolymers was analysed. It was reported

that, similar to the effect obtained on drug delivery kinetics, it was possible to

modulate mechanical properties of materials by varying the molar ratio between co-

monomers. Results showed that the effect of macromolecular composition on the

mechanical behaviour could be studied using the equations derived from the thermal

Fig. 6 Empirical model proposed for all FA loadings: a 1 % (correlation: 1.000); b 5 % (0.996); c 10 %(0.997)

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analysis. In particular, Eq. (2), derived from the Gordon–Taylor model, could be

used to predict the variation of the Young’s modulus by varying the weight fraction

of the two co-monomers with a good correlation between experimental data. It is

significant to point out that the same model was previously used to predict the Tg in

these copolymers with good results. In addition, the effect of a solute loaded within

matrices acted as plasticiser and caused a lowering of both the glass transition

temperature and the Young’s modulus. Results suggested that the thermomechanical

characterisation of drug-loaded matrices results fundamental when a polymer is

considered a potential candidate to obtain coatings for DES because mechanical

strength may significantly vary. However, tensile tests are not sufficient to

understand the behaviour of a complex thin coating for a DES. As reported,

copolymers analysed in the present work were previously characterised to evaluate

drug release properties [23], cyto- and haemo-compatibility [25] and some in silico

models were already studied to evaluate stresses and strains occurring after the stent

deployment in an occluded artery [30]. The future application of the present study

will be the accurate description of the structural behaviour of these copolymers in

silico models. In addition, in future works other different properties, such as the

adhesion of the coating on the metallic surface of the stent, the feasibility of a

coating on commercial DES and the optimisation of polymer/drugs formulations,

will be explored to evaluate the possibility to realise a commercial device using the

novel synthesised P(MMA-co-BMA) copolymers.

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