Acrylic Copolymers as Candidates for Drug-Eluting Coating of Vascular Stents

Acrylic Copolymers asCandidates for Drug-ElutingCoating of Vascular Stents

D. SILVESTRI,1,3,* C. CRISTALLINI,2 M. GAGLIARDI,1

N. BARBANI,1 M. D’ACUNTO,1 G. CIARDELLI4

AND P. GIUSTI1,2,3

1Department of Chemical Engineering, Industrial

Chemistry and Materials Science, University of Pisa, Italy2CNR Institute for Composite and Biomedical Materials IMCB

Pisa, c/o Department of Chemical Engineering, Italy3Interdepartmental Centre for the study and evaluation

of Biomaterials and Endo-prosthesis

‘Nicolino Marchetti’ (C.I.B.E.), Pisa, Italy4Department of Mechanics, Politecnico in Turin, Italy

ABSTRACT: The aim of the present work is the synthesis and characterizationof polymer materials showing good adhesion, drug loading, and deliveryproperties, for potential cardiovascular application. In particular, poly(methyl-methacrylate-co-acrylic acid) copolymers are prepared in different compositionsby a radical polymerization and investigated as potential materials to coatmetallic stents and to carry out a local drug release. Films obtained by dissolvingthe copolymer in an appropriate organic solvent (also loaded with ananti-restenosis drug, such as tacrolimus) are investigated: physicochemicalproperties, adhesiveness to metallic stent material, and kinetics of drug releasein physiological environment are studied.

KEY WORDS: drug-eluting stents, polymeric coating, polymer–metaladhesion, controlled drug release.

*Author to whom correspondence should be addressed.E-mail: [email protected] 3 appears in color online: http://jba.sagepub.com

JOURNAL OF BIOMATERIALS APPLICATIONS Volume 24 — November 2009 353

0885-3282/09/04 0353–31 $10.00/0 DOI: 10.1177/0885328208095198� The Author(s), 2009. Reprints and permissions:http://www.sagepub.co.uk/journalsPermissions.nav

INTRODUCTION

Cardiovascular diseases are mainly caused by too much choles-terol in the bloodstream, which can build up an atherosclerotic

plaque inside the blood vessel walls and can reduce the available areafor blood flow, resulting, at worst, in coronary artery obstruction [1,2].In order to treat this coronary artery obstruction, usually a standardangioplasty technique is used. The clinical efficacy of simple angioplastyis limited by acute vessel occlusion and restenosis problems in the first 6months [3]. To reduce these deficiencies a new clinical therapy has beenintroduced with the implantation of metallic cardiovascular stent. A stentis an expandable tubular wire mesh [4–6] used for keeping open avessel after balloon angioplasty [7,8] and restoring the flow conditions [9].After stent implantation an inflammatory response could occur, causingneointimal proliferation, known as restenosis [10,11]. Restenosisrepresents a special case of atherosclerosis [12] and it is the mostimportant long-term issue after stent implantation, occurring in 15–60%of patients [13,14]. Restenosis poststenting, also called ‘in-stent reste-nosis,’ is mainly due to neointimal hyperplasia, uncontrolled proliferationand migration of smooth muscle cells and deposition of extra-cellularmatrix, with narrowing of vessel diameter [11,15].

The restenotic event represents the most common clinical problemafter stent implantation and its underlying mechanisms are not fullyunderstood. Probably, this uncontrolled growth could be associated withthe stretching of the vessel wall [16], the injury of the inner layer causedby the deployment of the stent [10,16,12,17], the inflammatory responseof the tissues [18] or the stent configuration [19,20].

Other studies [21–23] identified a relationship between blood flow instented arteries and restenosis.

The reocclusion of the vessel can be prevented by a local delivery ofdrugs able to inhibit the tissue growth. On this road, more recently drug-coated stents has been used to significantly reduce such incidences of re-occlusion [24–26]. Stents coated with a polymer layer loaded with activeagents such as rapamycin [27,28], paclitaxel [29,30] or tacrolimus[31,32] (employed for example in Janus Carbostent of Sorin BiomedicaCardio SpA) are commonly used for the restenosis. Also, using acoronary stent for local delivery of drugs (drug-eluting stents – DES) it ispossible to combine the effective scaffolding of metallic structure withthe action of targeted drug delivered from a suitable polymeric coatingplatform, taking advantage from the direct contact with the vessel wall.

Coatings may be classified into synthetic polymers, biologicalmaterials, and inorganic coatings. In the family of synthetic polymers,

354 D. SILVESTRI ET AL.

used polymers are for example poly(-n-butyl methacrylate) (PBMA)and poly(ethylene vinyl acetate) (PVAc) for sirolimus release andpoly(lactide-co-TM-caprolactone) for Paclitaxel elution [25]. Anotherinteresting class of polymers used for biomedical applications isrepresented by MPC polymers: this 2-methacryloyloxyethyl phosphor-ylcholine-containing materials exhibited an excellent blood compatibility[33–37], a reduced platelet deposition [38–40], a limited neointimalhyperplasia [41,42] and good results if used as stent coatings [43,44].

The ideal coating should allow drug storage and release withoutinterfering with any biological process. Nevertheless, the idea of aphysiologically inert coating is difficult to realize, and there is clearevidence of potential toxic and inflammatory responses of the vessel wallto some substances used [45].

Our research originates from the necessity to find and to studynovel polymeric materials for drug elution from cardiovasculardevices, investigating the chemical properties of material and thepossibility to store and after to release drugs from polymeric coating.The aim of the present work is to present methods for testing theadhesion and drug delivery characteristics of synthesizedpolymeric materials, based on methylmethacrylate MMA and acrylicacid AA. Concerning acrylic polymers, previous studies showedgood characteristics of poly methyl methacrylate as biomaterial [46]for its high hemo and biocompatibility [47] and the capabilityin controlling the drug release as homopolymer or when used asco-monomer in copolymer syntheses [48,49]. Moreover, poly acrylic acidis used as co-monomer for improve physicochemical capabilities ofbiomedical materials [50–52]. Copolymer of methyl methacrylate andacrylic acid P(MMA-co-AA) was also investigated for biomedical uses[53,54] but never as stents coating.

In the present work, the synthesized materials were compared interms of adhesion characteristics to stent strut with other commerciallyavailable materials (investigated for cardiovascular stent covering), suchas poly(buthylmethacrylate) (PBMA) [55,56], poly(vinyl alcohol) (PVA)[57], poly(ethylene-co-vinyl alcohol) (EVAL), and poly(methyl metha-crylate) (PMMA) [58,59] but for the sake of shortness of the paper wereported the results concerning newly synthesized materials onlycompared to commercial origin PMMA.

In this paper, the adhesion of P(MMA-co-AA) copolymers on metallicsurfaces of stents was reported. Also, paclitaxel and tacrolimus deliverytests from poly(methyl methacrylate) (PMMA) and poly(methyl metha-crylate-co-acrylic acid) [P(MMA-co-AA)] in different molar percentagecompositions (90 : 10 and 70 : 30) were illustrated and discussed.

Drug-Eluting Coating of Vascular Stents 355

MATERIALS AND METHODS

Materials

Polymeric MaterialsPolymers used for tests were: PMMA (PMMAc, commercial origin –

120,000 Da, Sigma Aldrich�), synthesized PMMA (PMMAs, 670,000 Da,evaluated by GPC analysis), and P(MMA-co-AA) copolymers 90 : 10(720,000 Da) and 70 : 30 (740,000 Da).

Noncommercial PMMA and P(MMA-co-AA) copolymers wereobtained through a suspension polymerization by a radical reaction indeionized water (suspension medium). Methyl methacrylate (MMA,Sigma Aldrich�, molecular weight 100.12 g/mol, specific gravity 0.94 g/cm3) and acrylic acid (AA, Sigma Aldrich�, molecular weight 72.06 g/mol, specific gravity 1.05 g/cm3) were purified by distillation in vacuumto remove the polymerization inhibitor and used as reacting monomers.2-Hydroxy ethyl cellulose (HEC, Aldrich Chemical Company Inc.�)as stabilization agent and benzoyl peroxide (BPO, Sigma Aldrich�) asradical initiator, were employed. The amount of monomers were selected(as indicated in Table 1) to obtain three different composition of the finalmaterial: in particular the monomers (total moles: 0.933) were added to500 mL of water, together with 2.4 g of HEC and 450 mg of BPO.

The reaction was carried out in a glass reactor at 708C (controlled by athermo couple) using a Rushton impeller, moved by a Heidolf RZR2020 engine. The time of reaction was 3 h: after this time, reactortemperature was increased until 908C and maintained for another 3 h.

Table 1. Preparation of acrylic copolymers: starting conditions and finalconversion of monomers.

Polymerization mixtures

(co)polymernomenclature

MMA(mol)

AA(mol)

Reaction solvent:water (mL)

HEC(g)

BPO(g)

PMMAc Commercial origin polymerPMMAs 0.933 – 500 2.4 0.45P(MMA-co-AA) 91 0.84 0.093 500 2.4 0.45P(MMA-co-AA) 73 0.653 0.28 500 2.4 0.45

Final conversion of monomers(co)polymer nomenclature MMA (%) AA (%)PMMAs 99.6 –P(MMA-co-AA) 91 98.7 98.3P(MMA-co-AA) 73 97.9 98.1


At the end of the reaction final conversion of monomers was controlledby mean of HPLC method, checking the amount of residual reagents inthe reaction mixture.

Solvents and DrugSolvents used to obtain polymer solutions and polymer/drug

blends were: dichloromethane (CH2Cl2, Carlo Erba Reagenti�), iso-propanol (Isop, Carlo Erba Reagenti�), methylethylketone (MEK, CarloErba Reagenti�), bi-distilled water (H2O), dimethylsulfoxide (DMSO,Riedel de Haen�), tetrahydrofuran (THF, Sigma Aldrich�), dichlor-oethane (C2H4Cl2, Carlo Erba Reagenti�). Solvents used were of HPLCgrade purity.

Drugs used to obtain polymer/drug blends was Tacrolimus (TC),purchased by Sorin Biomedica Cardio S.p.A., and Paclitaxel (PLX)(Sigma Aldrich).

Methods

Preparation of Polymeric SolutionsFor testing adhesion behavior, various types of tests were carried out

on films prepared with different polymers. In particular, PMMAc andsynthesized polymers were dissolved in different organic solvents (withdifferent concentration) to study the effect of selected solvent andconcentration on adhesion characteristics of final polymeric coating. Forexample polymers were dissolved in CH2Cl2, DMSO, THF, C2H4Cl2, Isop-MEK 1 : 1 v/v mixture, varying the concentration from 1% to 5% (w/v); interms of solubility and final viscosity of solutions, the mixtures obtainedby using CH2Cl2 and Isop-MEK 1 : 1 mixture with 2% w/v concentrationwere preventively selected (and reported in Table 2). Concerning theadhesion characterization, after organic solvents selection, the followingtests were planned and carried out: contact angle test; test inphysiological solution; force–distance test by atomic force microscopy(AFM); cross-cut test; peeling test. Tested polymers and polymer–drugblend solutions employed for this research were reported in Table 2.

For drug delivery tests films were cast from a CH2Cl2 solution with 2%w/v polymer concentration containing paclitaxel or tacrolimus (10% w/wwith respect to polymer content) shed onto stainless steel AISI 316L andCarbofilm� substrates. Solution volume shed for the casting was 50 mL,and the deposition area was maintained the same for each sample.

In order to prevent voids formations and nonhomogeneous zonesacross the film thickness, a controlled casting process was performed,maintaining the sample at a fixed temperature (258C) and in a fan


furnace. The thickness of obtained films (coatings) was measured with acalliper (dimension range of 10� 1mm).

Contact Angle TestThe aim of wettability knowledge of a solid substrate is to investigate

how polymer solution spreading influences adhesion of final polymericcoating, achieved for casting, on a metallic or Carbofilm surface (forexample in the case of a dip-coating or spreading process). Two kind ofsolid surfaces were utilized in this test, AISI 316L (surface roughness of16–18 nm, evaluated by AFM analysis) and Carbofilm (14–19 nm).Preventively, surfaces were carefully prepared, polished and cleanedwith bi-distilled water and after with acetone. All surfaces were flat andwithout imperfections. With regard to liquid phases, pure solvents,polymer solutions, polymer/drug blends, and drug solutions (Table 2)were utilized. Pure solvents data were important to understand thesolvent influence on polymer solution behavior.

Liquid–vapour tensions and contact angle evaluation were performedin CAM200 KSV Instrument equipped with a digital camera. For liquid–vapor tension, evaluation is performed by drop shape method, this lastresulting from a balance of forces involving surface tension. In thepresent work, the cohesion energy (g) and the liquid–gas interfacialenergy (gLG) for solutions and blends were considered equal to puresolvents value. This is a reasonable simplification because all solutionsand blends are so diluted, that specific gravity resulted the same for thesolutions and corresponding solvent.

Table 2. Preparation of solutions and nomenclature of final obtained systems.

PolymerConcentration

(w/v) Solvent

Nomenclature offinal coating

sample

PMMAc (%) 2 CH2Cl2 PMMAc-1PMMAc (%) 2 Isop-MEK (1 : 1 v/v) PMMAc-2PMMAs (%) 2 CH2Cl2 PMMAs-1PMMAs (%) 2 Isop-MEK (1 : 1 v/v) PMMAs-2P(MMA-co-AA) 91 (%) 2 CH2Cl2 COP91-1P(MMA-co-AA) 91 (%) 2 Isop-MEK (1 : 1 v/v) COP91-2P(MMA-co-AA) 73 (%) 2 CH2Cl2 COP73-1P(MMA-co-AA) 73 (%) 2 Isop-MEK (1 : 1 v/v) COP73-2P(MMA-co-AA) 91þ TC (%) 2 (1 : 1) CH2Cl2 (COP91þTC)-1P(MMA-co-AA) 91þ TC (%) 2 (1 : 1) Isop-MEK (1 : 1 v/v) (COP91þTC)-2P(MMA-co-AA) 73þ TC (%) 2 (1 : 1) CH2Cl2 (COP73þTC)-1P(MMA-co-AA) 73þ TC (%) 2 (1 : 1) Isop-MEK (1 : 1 v/v) (COP73þTC)-2


For contact angle evaluation, each sample (solvent, polymer, orpolymer/drug on support) was placed onto a flat surface between cameraand bright source by a micro-syringe (5 mL in this experiment). Dropprofile was acquired onto a computer calculating contact angle, liquidsurface tension and volume: final measurement was obtained as meanbetween 12 values.

Test in Physiological SolutionPolymer solutions reported in Table 2 were prepared and deposited on

‘stent material’ supports, and the casting solvent evaporated atcontrolled temperature (258C): in particular, 50 ml of polymer solutionor polymer/drug blend were uniformly shed onto the support andsubjected to a controlled casting.

Solid supports employed were stainless steel AISI 316Land Carbofilm-coated supports. Adhesion tests in physiologicalsolution were conducted by immersing the sample in a buffersolution with pH¼ 7.4 containing 0.05% w/v of sodium dodecyl sulphate(SDS). Each sample was maintained in a thermostatic and stirredbath at a temperature of 378C and all samples were monitoredevery 24 h, over the whole period in which the polymeric filmshowed adhesion onto the surface. The maximum period of monitoringwas 30 days.

Force–Distance Test by AFMIn AFM, elastic probe deflection in contact with a sample by the tip

was evaluated (Figure 1(a)). The deflection is directly proportional toforce between sample and tip [60].

AFM allowed evaluating force of adhesion between two kind ofmaterials by force-distance curves, as indicated in Figure 1(b).

When tip approaches the surface, some phenomena occur (Figure 1(a)):at first, probe deflections (x) make the distance (d) between tipand sample different, and from initial distance (z) the tip arrives incontact with sample when x¼ 0. Pushing away or drawing up thetip from the surface sample, two discontinuity points are showed onForce (F)–Distance (X) plot (Figure 1(d)). If tip is draw up a contactjump is showed (E), while pushing away the tip detachingjump occurs (Fadh), showing the force–distance curves an hysteresis(Figure 1(d)).

Mechanical contact analysis between two surfaces, in the presence ofadhesion or not, starts by considering a simple contact between a sphereand a flat surface. This model is suitable for schematization AFM tip andsample surface contact.


In this work, we used pyramid-shaped tips with a 40 nm radius. Tipwas drawn up and pushed away from substrate (AISI 316L andCarbofilm immersed in buffer solution with pH¼ 7.4 containing SDS)several times.

Practically, adhesion force between polymers and substrate wasevaluated in this way:

1. Coverage of AFM tip with the polymer of interest [an example isshown in Figure 1(c)]. The tip was first immersed in HNO3, after inamino propyltriethoxysilane (APTES) for obtain a thin coating thatworks as a glue, finally the tip was immersed in the polymer solutionof interest (solvent: CH2Cl2).

2. Morphological analysis by scanning electronic microscopy (SEM) forquantification of dimension of tip radius by Image ProPlus software;

3. Force–distance curve acquisition by AFM.

Sample

d

F

C

B

D X

A

E

Fadh

z

Force(a)

(c) (d)

(b)

Repulsive force

Attractive force

Distance

Non-contact

Contact

x

Figure 1. Force–distance test by AFM: (a) probe deflection during tip approach ontosample surface, (b) interaction force between tip and surface, (c) AFM tip coated by

PMMAs: initial radius value was about 40 nm, after coating 50–70 nm (evaluated by Image

ProPlus software), (d) typical force–distance curve obtained by AFM analysis.


Cross-Cut TestIn cross-cut method, the coating (prepared as indicated in Contact

Angle Test section) was cut into small squares by a bistoury cutter,thereby reducing lateral bonding, and after it was rip out with adhesivetape, according with UNI EN ISO 2409 regulation (regulating the wayfor coating strength evaluation during detachment from a surface whena squared grid is preventively impressed on it), to evaluate the adhesionproperties of coating on substrate. For test execution, an appropriatetool was used as cutter for scratching of coating. Substrates used wereAISI 316L and Carbofilm and polymers used were PMMAc, PMMAs,P(MMA-co-AA) 91, and 73, dissolved in CH2Cl2.

In particular, 30 mL of polymer solution were homogeneously shed onthe substrate, to obtain a 10 mm thickness. When solvent was evaporated,polymer was manually scratched by the cutter, paying attention to havean equal space between scratches in both directions.

Adhesion evaluation depends on the amount of polymer coating pulledout from support by adhesive tape. Qualitatively, as indicated by UNI ENISO 2409, adhesion can be defined as (Figure 2): excellent adhesion (cutedges are completely undamaged or show unimportant damages; Goodadhesion): small fragments detachment occurs (not above 5%); mediumadhesion (coating is detached on edges and on their intersections, notabove 15%); small adhesion (partial or complete coating detachmentoccurs on edges or within the squares, not above 35%); poor adhesion(great fragments are detached on edges; some square area is partially orcompletely detached, not above 65%).

The final qualitative evaluation is performed by optical microscopeWild M3Z.

Peeling TestPeeling test allowed the estimation of relative adhesive forces. In most

cases, this test is used for comparing various surface treatments.It consists in evaluating peel-off force when a coating is pulled out from a

Excellent Good Medium Small Poor

Figure 2. Qualitative evaluation of adhesion by cross-cut test (in accordance with UNIEN ISO 2409).


solid surface by operating with constant angle. Instrumentation used forpeeling tests was INSTRON 1181. In this contest, sample was composedby two solid flat and thin substrates (solid AISI 316L or Carbofilmsupports), arranged as reported in the part (c) of Figure 3. Betweenthem, polymer solution was shed and, after casting, polymer film stuckthe substrates.

Substrates superposition takes place immediately after 50mLpolymeric solution deposition (this volume was optimized to havea 10 mm in thickness polymer layer), leaving free two edges for grabbingby instrument vices, paying attention that superposition lengthswere equal for all samples. This arrangement allows considering

(a) (b)

(c)a) Thermostatic oven (37°C)b) Extensometer INSTRON 1181 inside the oven

Typical resulting peeling test graph

c) Thermostated peeling test by INSTRON

Force atdetachment

00

103045607590

0.1 0.2 0.3

Run (mm)

For

ce (

N)

0.4 0.5

Detachmentpoint

Polymerlayer

Metallicsamples

F

F

Figure 3. Schematization of thermostated peeling test (a, b) and scheme (c) of sample

employed for the test.


polymer as an adhesive. The polymer deformation is much higher thanmetallic supports deformation because high rigidity of the supports,while the polymer was assumed to have an elastoplastic behavior with alow yield stress.

Then, these forces cause a normal and a shear stress near the jointedges. When the joint unglues, force of adhesion between polymer(adhesive) and support surface (adherent) is not enough great forbalancing the couple of forces externally applied. On each sample twogauges were applied, one of these longitudinal, the other onetransversal, with respectively strokes of 5 and 2.5 mm.

In Vitro Drug ReleaseIn order to deepen the knowledge of drug delivery properties of these

materials, in addition to TC delivery, PLX release from characterizedpolymeric matrices was analyzed. Drug delivery tests were carried outby immersing the samples in a phosphate buffer solution with pH¼ 7.4containing 0.05% w/v of SDS. The SDS surfactant was added in thedelivery medium to increase the solubility of paclitaxel and tacrolimus inwater. Samples were maintained in a thermostatic and stirred bath at atemperature of 378C for all the testing period. Withdraws were carriedout during an established period of 20 days and the delivery solution wassubstituted on each withdraw.

Drug released amounts were measured by HPLC method. Apparatusconsisted of a 410 LC pump, an ALLTECH C18 5U column with anon-polar phase (dimensions 250 mm� 4.6 mm) and an UV detector(Perkin–Elmer).

Reagents used were specific HPLC grade acetonitrile (ACN, CarloErba Reagenti�) and deionized water. Operative conditions weredifferent for paclitaxel and tacrolimus. For paclitaxel, the mobilephase was 52% ACN and 48% water, paclitaxel observed retentiontime was about 3 min, internal flux rate was 1 mL/min, injected volumewas 100 mL and wavelength was 230 nm at room temperature.

For tacrolimus, the mobile phase was the same of paclitaxel,tacrolimus retention time was about 4.5 min, internal flux rate was1 mL/min, injected volume was 100 mL and utilized wavelength was205 nm at room temperature.

Mathematical Interpretation of Drug Delivery ResultsExperimental results were interpreted using a mathematical

model valid for biostable and nonporous polymeric matrices. Thedelivery kinetic of a drug from a polymeric biostable and nonporousmaterial is generally governed by a diffusion mechanism [61] and the


Equation (1) can be used for calculation of release constant k and releasekinetic order n:

Mt

M0¼ k � tn ð1Þ

In this equation, c is the drug concentration in the delivery solution, t isthe time, k is the kinetic constant characteristic of the drug/polymersystem, and n the characteristic coefficient which depends on the solutetransport mechanism. In particular, the kinetic order is an experimentalvalue correlated to the number of molecules implicated in the diffusionphenomenon, while the kinetic constant represents the diffusion rate ofdrug macromolecules.

Since drug release kinetic is different for each polymer/drug system,constants k are not comparable with them. For this reason the meandissolution time (MDT) was evaluated using the Mockel and Lippoldequation [62]:

MDT ¼n

nþ 1� k�1=n ð2Þ

The MDT reflects the dissolution time for the drug and it is an accurateparameter for drug release rate description, also it characterizes theretarding efficacy of the polymer matrix.

After kinetic parameters evaluation, the diffusivity coefficient D [63]was evaluated:

D ¼� � s2

t�

ffiffiffiffiffiffiffiffiffiffiffiffiffiMt

4 �M0

sð3Þ

where, s is the coating thickness.

RESULTS AND DISCUSSION

Contact Angle Test

Contact angle measurement of casting solvents and polymer solutionsresulted to be relevant from both practical and theoretical point of view.From the contact angles, in fact, it depends on the extent of contact areabetween liquid and solid and this knowledge can also be used to estimatesome parameters such as adhesion or friction between liquid dropletsand solid substrate.


By contact angle (�), cohesion energy (g), and liquid–gas interfacialenergy (gLG) measurements, it was possible to calculate the workof adhesion (Wa ¼ � � 1þ cos �ð Þ), the work of cohesion (Wc ¼ 2 � �),the work of spreading (Ws ¼ � � cos � � 1ð Þ) and the wetting tension(� ¼ � LV � cos �).

Pure SolventsAt first, properties and behavior of pure solvents were analyzed.

Results are quoted in Table 3.Work of adhesion refers to the free energy difference between two

specified states, the former in contact in equilibrium and the secondcomprising the two phases separated in equilibrium in vacuum [64],then it is a measure of interaction entities between liquid molecules andit depends on the solid surface. If work of adhesion is high, liquid andsolid surface present larger affinity. About this, it was reasonablydeducible that CH2Cl2 had higher affinity for Carbofilm than AISI316L, while Isop-MEK blend showed bigger affinity for AISI 316Lcompared to Carbofilm.

The evaluation of the work of spreading is important to estimate thepossibility to shed uniformly and homogeneously polymer solutions, forexample, during dip coating or spreading procedure. In this contest,considering the obtained results, both CH2Cl2 and Isop-MEK blendare good solvents.

Work of wetting (wetting tension) is the only parameter thatdepends on the balance between adhesion and cohesion forces but alsoon only liquid phase forces balance. For both surfaces, this parameterwas similar for two solvents used.

Polymeric SolutionsFrom the results of contact angle measurements, obtained for polymer

and polymer–drug solutions, it was possible to assume that the presenceof the polymer affects greatly the wettability of the surfaces. Carbofilmsurfaces exhibited, in most cases, higher wettability than AISI 316Lsurfaces when the cast solvent is CH2Cl2; on the contrary, for thesame polymer materials or polymer–TC blends, obtained starting froma solution in Isop-MEK, the surface that showed higher wettabilityand lower contact angles was AISI 316L (excluding only (COP91þTC)-2sample, where the contact angle resulted very similar for AISI 316Land Carbofilm).

Compared to pure solvents, polymeric solutions showed higher contactangle values. This behavior was attributed to the viscosity of thepolymer solutions. Compared to P(MMA-co-AA) 91 copolymer solutions,


Tab

le3

.C

on

tac

tan

gle

san

dth

erm

od

ynam

icp

ara

me

ters

for:

(a)

pu

reso

lve

nts

,(b

)p

oly

me

ran

dp

oly

me

r-d

rug

solu

tion

s,(c

)TC

dru

gso

lutio

ns

she

do

nto

AIS

I3

16

Lan

dC

arb

ofil

msu

pp

ort

.

Pu

reso

lve

nts

Sa

mp

leS

olv

en

tS

ub

stra

teC

on

tact

an

gle

(�)

(8)

g(m

N/m

)g L

V

(mN

/m)

Wa

(mN

/m)

Wc

(mN

/m)

Ws

(mN

/m)

�

(mN

/m)

CH

2C

l 2A

ISI

316L

18.5

34.7

421.3

69.2

39.4

8�

0.2

420.2

5C

arb

ofil

m11.2

610.0

119.8

220.0

2�

0.1

920.9

4Is

op

-ME

KA

ISI

316L

8.9

510.2

918.4

320.4

620.5

8�

0.1

218.2

2C

arb

ofil

m10.1

25.3

510.6

210.7

0�

0.0

818.1

6

Po

lym

er

an

dp

oly

mer-

dru

gso

lutio

ns

PM

MA

c-1

CH

2C

l 2A

ISI

316L

91.4

84.8

1�

4.6

70.3

3C

arb

ofil

m64.1

614.6

3�

5.3

99.8

7P

MM

Ac-

2Is

op

-ME

KA

ISI

316L

66.4

714.6

8�

5.9

07.8

6C

arb

ofil

m69.7

37.3

6�

3.3

46.9

3P

MM

As-

1C

H2C

l 2A

ISI

316L

89.5

34.9

7�

4.5

11.0

4C

arb

ofil

m61.8

914.9

7�

5.0

510.5

9P

MM

As-

2Is

op

-ME

KA

ISI

316L

54.5

616.4

6�

4.1

211.0

5C

arb

ofil

m64.7

37.7

7�

2.9

38.3

5C

OP

91-1

CH

2C

l 2A

ISI

316L

67.5

06.6

9�

2.7

98.7

7C

arb

ofil

m59.6

715.3

0�

4.7

211.2

8


(CO

P91þ

TC

)-1

CH

2C

l 2A

ISI

316L

32.2

68.7

8�

0.7

018.2

1C

arb

ofil

m30.8

918.6

7�

1.3

518.4

8C

OP

91-2

Iso

p-M

EK

AIS

I316L

43.3

917.9

1�

2.6

713.6

4C

arb

ofil

m53.3

98.6

4�

2.0

611.3

5(C

OP

91þ

TC

)-2

Iso

p-M

EK

AIS

I316L

15.9

020.2

1�

0.3

717.7

6C

arb

ofil

m15.0

210.5

3�

0.1

717.8

3C

OP

73-1

CH

2C

l 2A

ISI

316L

42.7

98.2

8�

1.2

015.9

5C

arb

ofil

m36.7

218.1

3�

1.8

917.3

3(C

OP

73þ

TC

)-1

CH

2C

l 2A

ISI

316L

34.0

09.9

4�

1.6

715.4

4C

arb

ofil

m31.7

718.9

1�

0.7

615.8

1C

OP

73-2

Iso

p-M

EK

AIS

I316L

40.6

018.2

2�

2.3

614.2

1C

arb

ofil

m43.8

99.2

8�

1.4

213.5

3(C

OP

73þ

TC

)-2

Iso

p-M

EK

AIS

I316L

16.4

120.1

8�

0.4

017.7

2C

arb

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m17.5

410.4

6�

0.2

417.6

2

TC

dru

gso

lutio

ns

TC

CH

2C

l 2A

ISI

316L

9.6

49.4

1�

0.0

621.0

5C

arb

ofil

m7.0

419.9

4�

0.0

721.1

9Is

op

-ME

KA

ISI

316L

7.5

020.5

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0.0

818.2

8C

arb

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110.6

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0.0

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0


P(MMA-co-AA) 73 showed higher capability to wet surfaces. Worksof adhesion for solutions in CH2Cl2 (and for Isop-MEK) were smallerthan pure solvents, indicating that the solutions have lower tendencyto interact and spread on the surfaces than pure solvent. Compared topure solvents, works of spreading decreased for all systems. Forsome systems, reductions of work of spreading were very evident,indicating a high variation of surfaces wettability. In this event,the highest variations were observed in systems without the presenceof the polymer.

After polymer addition, work of wetting (wetting tension) tends todecrease as regard with pure solvents in all cases. Furthermore, work ofwetting on Carbofilm is greater than AISI 316L after polymer additionwith CH2Cl2 solvent, while for Isop-MEK cast solution the results weremore random. Particularly interesting it resulted to be the effect of TCdrug addition: the simultaneous presence of drug and copolymer madethe values of the wetting tension more similar to pure solvents,especially for Isop-MEK solutions, probably for the variation in thestarting solution of the viscosity and the decreasing of interfacial energybetween liquid solution and solid surface. Therefore, for the solutionscontaining both drug and polymer, drug presence increased solutionaffinity towards surfaces, probably because it presents characteristicfunctional groups that make the solutions with higher affinity for carbo-coated or stainless steel surfaces.

By the comparison of solutions in CH2Cl2 and Isop-MEK blend,the positive behavior of the first solvent (and relative solutions) onCarbofilm was confirmed, like the higher affinity of the second one onAISI 316L. This could have an influence on the final adhesioncharacteristics of polymer coating for metallic stent surfaces.

Drug SolutionsWith the same method employed for pure solvents and polymeric

solutions, based on contact angle measurements, �, Wa, Ws, and � of TCdrug solutions were obtained and reported in Table 3.

It can be noted that drug solutions behavior was different from thatof pure solvents. For drug/CH2Cl2 and Isop-MEK solutions, contactangle decreased, indicating that the sample surfaces were more wettableby drug solution with respect to pure solvent. The values of works ofadhesion were very similar to the values of pure solvents, indicatingthat solvent affinity for surfaces did not vary by introducing the drug.Works of spreading were lower for CH2Cl2 solutions since solutionswetted the surfaces better than pure solvent; while these values showeda less evident variation using Isop-MEK blend as cast solvent.


Works of wetting confirmed pure solvents tendency, resultingapproximately the same for both surfaces tested. In any case the verylow contact angle of TC solution in both solvents confirmed and explainedalso the behavior of final polymeric coatings containing the drug(Table 4): in effect a decrease of the contact angle and an increase ofthe work of adhesion Wa (e.g., starting from a CH2Cl2 solution) wasobserved for samples containing the TC drug with respect to pure solventand drug-containing polymer coating.

Tests in Physiological Solution

The results of adhesion tests in physiological solution were reported inFigure 4. Tests were carried out under the same condition mentionedpreviously and the maximum duration of the test was 30 days. Fivesamples were analyzed to have a statistic validation.

It can be noted that the adhesion of polymeric films onto steel surfaceswas poor if compared to Carbofilm substrate. In fact, if adhesion testresults on AISI 316L supports are compared with those on Carbofilm;it can be observed that better results in terms of adhesion of polymericfilm on the surface were shown for Carbofilm supports: these resultswere connected and associated with the greater wettability of Carbofilmsurface (see Contact Angle Evaluation section).

Adhesion of PMMA-based polymeric films (in particular for synthe-sized PMMAs) did not show relevant changes at varying of the solventused for the polymers. Probably the surface adhesion in wet conditionsstrongly depends on the typology of polymer and not on the type ofsolvent or the deposition step and casting.

Adhesion test data in physiological solution showed results similar tothose obtained from contact angle measurements. Polymeric filmadhesion is better on the surfaces having a low value of contact angle(less wetting). Work of wetting shows lower values for systems havingpoor adhesion onto the support. Even works of adhesion have a similar

Table 4. Fd values obtained by peeling test.

Sample Surface Fd (N/mm2)

COP 73-1 AISI 316L 52.9COP 73-1 Carbofilm 68.7COP 91-1 AISI 316L 41.5COP 91-1 Carbofilm 48.9PMMAs-1 AISI 316L 11.2PMMAs-1 Carbofilm 34.9


trend: with the increasing of adhesion work of liquid solution, adhesionof polymeric film on the support increases too, confirming the goodperformances of polymer coatings (with or without TC drug) obtainedstarting from a solution in CH2Cl2, in particular on Carbofilm surface(the nanometric roughness, estimated by AFM, was practically the samefor Carbofilm and AISI 316L surfaces).

Concerning the effect of the composition of the polymer material oncoating resistance, with the increasing of acrylic acid percentage in themacromolecule a better adhesion was obtained. Actually, PMMA-basedcopolymer, containing the higher amount of AA functionality, reachedthe maximum durability of the test [see COP73-1, COP73-2, and(COP73þTC)-1 behavior]. Even for these systems, adhesion test datacan be directly correlated with contact angle results. Well-wettedsurfaces allowed a final good adhesion of the polymeric films.Furthermore adhesion and wetting works are higher for systemsshowing a good adhesion.

The presence of the drug, in some cases, influenced the performancesin adhesion of polymeric films onto the metallic supports. On Carbofilmmaterial, the drug presence changed the adhesion of polymeric films:adhesiveness decreased for COP73-2 system when polymer/drug blend(COP73þTC)-2 was utilized, but, for example, adhesion did not vary

PMMA−L−1

0

5

10

15

20

25

30

PMMA−L−2

PMMA−H−1

PMMA−H−2

COP91−1 COP91−2 COP73−1

Materials

Tim

e (d

)

COP73−2 (COP91+F)−1

(COP91+F)−2

(COP73+F)−1

(COP73+F)−2

AISI 316L

Carbofilm

Figure 4. Results of adhesion test in physiological solution (maximum time ofmonitoring, 30 days).


when the drug was added to systems COP73-1/(COP73þF)-1, COP91-1/(COP91þTC)-1 and COP91-2/(COP91þTC)-2. This behavior can beascribed to the different dissolution of tacrolimus drug in CH2Cl2 andIsop-MEK blend, confirming for example the good performance ofCH2Cl2 as starting cast solvent for drug-containing polymer coating.

From the results of contact angle and adhesion in physiologicalsolution, it can be concluded that CH2Cl2 is a better solvent (with morestable and reproducible results) than Isop-MEK blend for the finaladhesion of the coating on Carbofilm and AISI 316L. For this reason,all following tests were conducted using CH2Cl2 as solvent for startingcast solution.

Force–distance test by AFM

Force of adhesion between polymer and stent surface was evaluatedby force-distance curves as well. The test allowed quantifying attractionand repulsion forces between the tip of the AFM instrument coated withthe polymers of interest and a typical surface of coronary stent.

As reported, respectively for AISI 316L (Figure 5(a)) and Carbofilm(Figure 5(b)), the attraction and repulsion forces between the PMMAcpolymer and substrates resulted higher for Carbofilm than AISI 316L.

As showed in Figure 5(a), during approaching phase (data not shown)and removing phase (reported curve) of the tip from the sample, contactjump associated with detachment was not significant. The same testperformed onto Carbofilm surface exhibited, on the contrary, a relevantdetachment jump, associated with a force of adhesion of 0.09 nN, asreported in Figure 5(b).

Concerning PMMAs, the force–distance curves (Figure 5(c) and (d))exhibited the same behavior observed for commercial origin polymer,showing no evidence of interaction (at electrostatic level) withstainless steel material, while a higher interaction was detected withCarbofilm surface.

Moreover, for P(MMA-co-AA) 91, an adhesion force on Carbofilmwas observed, confirming the greater interaction of this polymermaterial with this surface with respect to AISI 316L. In particular,the introduction of carboxylic groups into the polymer chain (due tothe presence of AA as co-monomer) warranted an increase ofadhesion properties, with a quantitative increase of adhesiveness ofP(MMA-co-AA) 91 on Carbofilm; the force of adhesion increased from0.1 nN for PMMAc and PMMAs to 0.165 nN for P(MMA-co-AA) 91.

Finally, P(MMA-co-AA) 73 exhibited an adhesion force onto Carbofilmgreater than previous cases: in particular, the increase of carboxylic


group amount in the polymeric chain allowed a quantitative increase ofadhesion values [0.1 nN for PMMA, 0.165 nN for P(MMA-co-AA) 91 and0.25 nN for P(MMA-co-AA) 73]. So, for this it was also possible tomeasure the force of adhesion on AISI 316L, while no value it wasobtained for PMMA and P(MMA-co-AA) 91.

Figure 5. Evaluation of the adhesion forces between AISI 316L (column on the left) or

Carbofilm (column on the right) surfaces and AFM tip coated with PMMAc (a, b), PMMAs(c, d), P(MMA-co-AA) 91 (e, f ), and P(MMA-co-AA) 73 (g, h).


These results showed a force of adhesion greater for Carbofilm thanAISI 316L. Force of adhesion varies linearly with the copolymer compo-sition (Figure 6) and acrylic acid functionalities inside the material.

Cross-cut Test

The nature of the coatings did not permit to measure the weight of thepolymer detached with a sufficient precision. However, although theanalysis value is qualitative, some important indication to support andintegrate other adhesion results, and to carry out a classificationof different materials studied in terms of adhesiveness to stent material,was obtained.

Following (Figure 7), we reported a comprehensive view of the resultsobtained by means cross-cut test for all polymers of interest for this work.

Concerning PMMAc, images indicated a good adhesion on AISI 316Land poor on Carbofilm.

PMMAs showed low adhesion on all types of support. In particular,adhesion resulted to be poor on Carbofilm, where the amount of materiallost is greater than 65%.

Also P(MMA-co-AA) 91 showed low adhesion on AISI 316L andCarbofilm, with fragments detachment, even if an improvement ofadhesion was obtained by introducing carboxylic groups in thepolymer chain.

0.3

0.25

0.2

0.15

0.1

0.05

00 0.05 0.1 0.15

AA amount (fraction)

For

ce o

f adh

esio

n by

AF

M (

nN)

0.2 0.25 0.3

Figure 6. Force of adhesion on Carbofilm surface by AFM versus P(MMA-co-AA)

copolymer composition.


Finally, P(MMA-co-AA) 73 exhibited a good adhesion on AISI 316Land Carbofilm. This qualitative analysis showed and confirmed thepositive influence of carboxylic groups that increased the adhesivenessand interactions between stent surface and polymer coating, soimproving the performance of copolymer coating in terms of stabilityon metallic substrate.

Peeling Test

For a statistical study, three samples for each material were testedby this method. To compare directly the results of peeling test,detachment forces (Fd) were reported in Table 4: these values wereobtained normalizing the detachment forces measured by Instron, withrespect to reference area.

AISI 316L Carbofilm

Before After Before After

PMMAc

a.1 a.2 a.3 a.4

b.1 b.2 b.3 b.4

c.1 c.2 c.3 c.4

d.1 d.2 d.3 d.4

P (MMA-co-AA) 73

P (MMA-co-AA) 91

PMMAs

Figure 7. Results of cross-cut test for PMMAc, PMMAs, P(MMA-co-AA) 91, and P(MMA-

co-AA) 73 materials on stainless steel and Carbofilm surfaces.


In particular, results underlined how detachment stress increases inthe case of Carbofilm instead of AISI 316L, independently from thesample nature in agreement with experimental results of adhesion testin physiological solution and for coating obtained starting from asolution in CH2Cl2. If the adhesion onto solid substrate increases, infact, polymeric film showed greater strength during peeling tests and,however, detachment stress increased.

P(MMA-co-AA) 73 showed a greater detachment stress thanP(MMA-co-AA) 91 and PMMAs materials, so indicating that if acrylicacid percentage increased the traction strength increased, with apositive effect on the resistance and adhesiveness of polymer materialfor coating.

Drug Delivery Tests

Tacrolimus ReleaseFigure 8 shows the cumulative percentage of tacrolimus released by

each polymer matrix, compared to free drug release kinetic (without anypolymer matrix). This comparison gains in importance because there aresome commercial polymer-free devices, such as Janus Carbostent (SorinBiomedica Cardio S.p.A.), containing only tacrolimus. The tacrolimusdelivery directly in tissues is possible since its toxicity level is low and afast release from the device is not dangerous.

From this comparison it is important to emphasize that polymermatrices bred in any case a decrease on the control delivery rate becausean increase of delivery rate occurred when acrylic acid percentage in thecopolymer chain increased.

Kinetic parameters (n, k, D, and MDT) were calculated andsummarized in Table 5.

From n values it is possible to define as anomalous (n� 0.45) thetransport mechanism [65] for all polymers. The values of n indicatedthat the release of tacrolimus drug from acrylic matrices resulted to beintermediate between the classical Fickian mechanism for planar anddense polymer matrix and a zero-order delivery kinetic.

Also, k and MDT were found to be functions of polymer composition:increasing acrylic acid percentage, the kinetic constant increased whilethe mean dissolution time decreased.

Paclitaxel ReleaseFigure 9 shows the cumulative percentage release of paclitaxel

from each polymer matrix. A free paclitaxel release in an implanteddevice is not indicated because of highly toxicity of the drug [66,67].


For this reason, free release kinetic in this work was neglected.Results obtained indicated that also for paclitaxel, as tacrolimus, itwas possible to control the drug delivery rate by varying percentagecomposition of copolymer macromolecules: in particular, obtainedresults indicated and confirmed the significant role played by thepresence of carboxylic groups on the polymer chain in affecting thedrug elution mechanism. This effect was more evident withrespect to tacrolimus drug, showing the paclitaxel to be practicallyretained by pure PMMA matrix, while a cumulative release of 4 and14% (after 20 days) was detected for P(MMA-co-AA) 91 and 73copolymers, respectively. Kinetic parameters k and n for all samplesare reported in Table 6.

100

90

80

70

60

50

40

30

20

10

00 5 10

Time (d)

Tacr

olim

us r

elea

sed

(%)

PMMA P(MMA-co-AA) 91 P(MMA-co-AA) 73 Free

15 20

Figure 8. Cumulative delivery of ‘free’ Tacrolimus compared with delivery from PMMA,P(MMA-co-AA) 91, and P(MMA-co-AA) 73 matrices.

Table 5. Kinetic parameters for Tacrolimus delivery evaluatedusing a bi-logarithmic plot: kinetic order, kinetic constant, mean

dissolution time, and diffusion coefficient.

Materials n k (1/d) MDT (d) D (m2/d)

PMMA 0.61 0.26 3.43 2.42� 10�10 (�2� 10�11)P(MMA-co-AA) 91 0.76 0.33 1.82 3.65� 10�10 (�5� 10�11)P(MMA-co-AA) 73 0.62 0.458 1.40 4.56� 10�10 (�7� 10�11)


For paclitaxel, n values identify a Fickian transport mechanism(n� 0.45) for all polymers [38], indicating that matrix interacts with thedrug, avoiding its rapid elution in the delivery medium (clearly, the lowsolubility of paclitaxel played a fundamental role in the observed drugelution results). Also, n was not found to be a function of polymercomposition, remaining practically constant with respect to polymericmaterial composition.

With regard to the MDT, its value decreased increasing the acrylicacid percentage, as observed for systems containing tacrolimus. Theobservations carried out for tacrolimus drug concerning diffusioncoefficient trend versus polymeric material composition can be extendedto paclitaxel release analysis.

00

3

6

9

12

15

5 10 15 20

Time (d)

Pac

litax

el r

elea

sed

(%)

PMMA P(MMA-co-AA) 91 P(MMA-co-AA) 73

Figure 9. Cumulative delivery of Paclitaxel from PMMA, P(MMA-co-AA) 91, and

P(MMA-co-AA) 73 matrices.

Table 6. Kinetic parameters for Paclitaxel delivery evaluatedusing a bi-logarithmic plot: kinetic order, kinetic constant, mean

dissolution time, and diffusion coefficient.

Materials n k (1/d) MDT (d) D (m2/d)

PMMA 0.21 3.56� 10�2 1.61� 106 1.83� 10�11 (�2� 10�11)P(MMA-co-AA) 91 0.23 1.74� 10�1 398 1.15� 10�10 (�1� 10�11)P(MMA-co-AA) 73 0.22 3.24� 10�1 32.6 2.35� 10�10 (�3� 10�11)


CONCLUSIONS

Adhesive properties are important for a preliminary screening of goodmaterials for polymer coating to be utilized for endovascular grafts.Different materials were synthesized and polymer-based coatingsprepared and tested for their potential application on coronary stents.Different typologies of adhesion tests were defined, improved andperformed to evaluate if these methodologies are successful incharacterizing the various types of coating materials on Carbofilm orother metal surfaces.

Concerning practical results by adhesion experiments, adhesion testsin physiological solution indicated a greater tendency of polymers tostick on Carbofilm surface than AISI 316L. Some samples remained onthe Carbofilm surface during the whole test (30 days) and this tendencywas observed in particular for P(MMA-co-AA) 73 containing a largeramount in acrylic groups with respect to other materials.

Contact angle evaluation allowed knowing the ability of a polymersolution to wet a solid surface and estimate the solid–liquid interactionsand confirmed the good characteristics of wettability of Carbofilmsurface, important requirement to achieve a good adhesion of the coating.

Force–distance curves revealed the existence of interactions betweenpolymer and surfaces at an atomic scale, confirming the behavior ofmaterials to be dependent on polymer chain composition and carboxylicgroups presence.

By comparing the results obtained from different types of the adhesiontests carried out, the possibility to control the adhesive performances ofthe materials studied by varying the deposition method (i.e., castingsolvent and/or acrylic polymer chain composition) was confirmed. Inparticular, CH2Cl2 cast solvent seemed to be a good candidate for thecoverage of a Carbofilm stent strut, for example in a dip-coating process,while P(MMA-co-AA) 73 based-material can be considered an optimumcandidate as polymer coating for carbo-coated stent.

Copolymers based on MMA and AA monomers were synthesized byvarying initial molar ratio of the reaction feed, with the additional goalto insert hydrophilic fractions inside hydrophobic PMMA chains. Theintroduction of carboxylic groups in the polymer material stronglyinfluenced the elution properties of material (in terms of cumulativeamount and kinetic).

Drug-elution test in buffer solution confirmed the effect ofthe macromolecular composition on cumulative release and on kineticof the delivery, with an increased release of paclitaxel andtacrolimus drugs by using the acrylic P(MMA-co-AA) copolymers with


respect to hydrophobic pure PMMA. Concerning drug delivery kinetic,the most efficacious composition in terms of AA content in the polymerchain has to be established carrying out in-vivo tests as well (the in vivoand in vitro tests provide in general different results in terms of releaserate). In any case, these materials showed in vitro to be promisingplatforms to entrap and after release in aqueous environment hydro-phobic and poor soluble drugs such as tacrolimus and paclitaxel.

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Acrylic Copolymers as Candidates for Drug-Eluting Coating of Vascular Stents