Interactions between Multivalent Ions and Exponentially Growing

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Interactions between Multivalent Ions and Exponentially Growing Multilayers: Dissolution and Exchange Processes Vincent Ball,*,† Eric Hu¨bsch,†,‡ Ru¨diger Schweiss,§ Jean-Claude Voegel,† Pierre Schaaf,‡ and Wolfgang Knoll§ Faculte´ de Chirurgie Dentaire, UMR 595, Institut National de la Sante´ et de la Recherche Me´ dicale, 11 rue Humann, 67085 Strasbourg Cedex, France, Max Planck Institut fu¨ r Polymerforschung, Ackermannweg 10, Mainz D-55128, Germany, and Institut Charles Sadron, Unite´ Propre 22, Centre National de la Recherche Scientifique, 6 rue Boussingault, 67083 Strasbourg Cedex, France Received April 1, 2005. In Final Form: July 5, 2005 The interactions between multivalent ions (small ions or polyelectrolytes) and two exponentially growing polyelectrolyte multilayers, namely, (HA-PLL)n and (HA-PAH)n films, are investigated (HA ) hyaluronic acid, PLL ) poly-L-lysine, PAH ) poly(allylamine)). Ferrocyanide and ferricyanide ions are used as small ion probes. The most striking finding is that, even though these two ions differ only by one charge unit, the ferrocyanide ions induce a partial dissolution of both multilayers whereas these films remain stable in the presence of ferricyanide ions. The dissolution process of (HA-PLL)n films is more rapid than that of (HA-PAH)n films, indicating a stronger interaction between HA and PAH compared to HA and PLL. This is confirmed by polyelectrolyte exchange experiments: when an (HA-PLL)n multilayer film is put into contact with a PAH solution, PLL is quantitatively exchanged with the PAH chains and transformed into an HA-PAH film, whereas an (HA-PAH)n multilayer remains stable in the presence of a PLL solution.

* To whom correspondence should be addressed. Phone: 0033 3 90 24 32 58. E-mail: [email protected]. † Institut National de la Sante ´ et de la Recherche Me´dicale. ‡ Centre National de la Recherche Scientifique. § Max Planck Institut fu ¨ r Polymerforschung.

of the neighboring layers as demonstrated by means of small angle neutron scattering experiments.11 The thickness increment per layer pair depends mainly on the physicochemical parameters of the solutions into which the polyelectrolytes are dissolved.12-14 In general, the layer thickness increases with the ionic strength9 at a given pH value. When weak polyelectrolytes are employed whose charge densities are functions of the solution pH and ionic strength, the maximum in thickness is reached when one of the polyelectrolytes is only partially charged whereas the other one is fully charged.12 The resulting thickness and swelling properties change considerably, which in turn presents interesting properties for biomedical applications.15 These linearly growing polyelectrolyte multilayers also possess interesting permeability properties: they favor the separation of ethanol/water mixtures if deposited on top of mesoporous membranes,16 and they are only slightly permeable to electroactive species.17-19 This permeability depends however on the salt concentration of the solutions from which the multilayers are deposited. In general, the permeability increases at higher salt concentrations, and it also depends on the sign of the last deposited layer with respect to the sign of the charge of the redox probe, as well as on the valency of the redox probe.17-19

(1) .Decher, G. Science 1997, 277, 1232. (2) Sukhorukov, G. B.; Donath, E.; Lichtenfeld, H.; Knippel, E.; Knippel, M.; Budde, A.; Mo¨hwald, H. Colloids Surf., A 1998, 137, 253. (3) Fou, A. C.; Onitsuka, O.; Ferreira, M.; Rubner, M. F.; Hsieh, B. R. J. Appl. Phys. 1996, 79, 7501. (4) Eckle, M.; Decher, G. Nano Lett. 2001, 1, 45. (5) Kotov, N. A.; Dekany, I.; Fendler, J. H. J. Phys. Chem. 1995, 99, 13065. (6) Benkirane-Jessel, N.; Schwinte, P.; Falvey, P.; Darcy, R.; Haı¨kel, Y.; Schaaf, P.; Voegel, J. C.; Ogier, J. Adv. Funct. Mater. 2004, 14, 174. (7) Chluba, J.; Voegel, J. C.; Decher, G.; Erbacher, P.; Schaaf, P.; Ogier, J. Biomacromolecules 2001, 2, 800. (8) Serizawa, T.; Yamaguchi, M.; Matsuyama, T.; Akashi, M. Biomacromolecules 2000, 1, 306. (9) Ladam, G.; Schaad, P.; Voegel, J. C.; Schaaf, P.; Decher, G.; Cuisinier, F. J. G. Langmuir 2000, 16, 1249. (10) Caruso, F.; Donath, E.; Mo¨hwald, H. J. Phys. Chem. B 1998, 102, 2011.

(11) Schmitt, J.; Gru¨newald, T.; Decher, G.; Pershan, P. S.; Kjaer, K.; Lo¨sche, M. Macromolecules 1993, 26, 8. (12) Yoo, D.; Shiratori, S. S.; Rubner, M. F. Macromolecules 1998, 31, 4309. (13) Shiratori, S. S.; Rubner, M. F. Macromolecules 2000, 33, 4213. (14) Schlenoff, J. B.; Ly, H.; Li, M. J. Am. Chem. Soc. 1998, 120, 7626. (15) Mendelsohn, J. D.; Yang, S. Y.; Hiller, J.; Hochbaum, A. I.; Rubner, M. F. Biomacromolecules 2003, 4, 96. (16) (a) Krasemann, L.; Toutianoush, A.; Tieke, B. J Membr. Sci. 2001, 181, 221. (b) Tieke, B.; van Ackern, F.; Krasemann, L.; Toutianoush, A. Eur. Phys. J. E 2001, 5, 29. (17) Fahrat, T.; Schlenoff, J. B. Langmuir 2001, 17, 1184. (18) Han, S.; Lindholm-Sethson, B. Electrochim. Acta 1999, 45, 845. (19) Pardo-Yissar, V.; Katz, E.; Lioubashevski, O.; Willner, I. Langmuir 2001, 17, 1110.

Introduction Over the past 10 years, the layer by layer (LBL) buildup of polyelectrolyte multilayers1 has become a very promising tool to modify the interfacial properties of solid surfaces of either planar or nonplanar geometries.2 Polyelectrolyte multilayers found applications, for example, in the field of electrooptical materials,3-5 in the design of bioactive material coatings,6,7 or to display pro- or anticoagulant properties by a single modification of the last deposited polyelectrolyte layer.8 The success of the LBL coating method is due to its large versatility: the method works reliably provided the substrate carries a nonzero surface charge density and multilayer formation proceeds via charge overcompensation after each layer deposition.9,10 Most of the investigated polyanion and polycation combinations exhibit linear growth of the assembly thickness with the number of deposited layer pairs. Linearly growing polyelectrolyte multilayer films display little interpenetration of the polyelectrolytes of a given layer with those

10.1021/la050866o CCC: $30.25 © 2005 American Chemical Society Published on Web 08/04/2005

Multivalent Ion-Growing Multilayer Interactions

An increasing number of studies have recently been devoted to the fabrication of LBL polyelectrolyte multilayers whose thicknesses increase exponentially with the number of deposited layer pairs.20-25 This peculiar behavior seems to result generally from the diffusion of at least one of the two polyelectrolytes through the whole film thickness at each bilayer deposition step as demonstrated by means of laser confocal scanning microscopy.22 Typical polyelectrolyte combinations leading to exponential film growth are hyaluronic acid (HA)-poly-L-lysine (PLL),21,22 poly-L-glutamic acid (PGA) [or poly-L-aspartic acid (Pasp)]-poly-L-lysine,25 and poly-L-glutamic acidpoly(allylamine) (PAH).24 Exponentially growing films are dynamic entities where diffusion and exchange processes can take place as in polyelectrolyte complexes.26 It has, for example, been shown that when a PSS-PAH bilayer (PSS ) polystyrenesulfonate) is deposited on top of a (PGA-PLL)n multilayer, PSS diffuses into the (PGAPLL)n film and exchanges partially with the PGA chains of the (PGA-PLL)n architecture.27 More recently, it was shown that when (PGA-PAH)n films are brought into contact with ferrocyanide-containing solutions, these ions diffuse into the film and are trapped by the multilayer.28 Ferrocyanide ions are well-known to interact with polycations and have been used to enhance the contrast in AFM imaging of individual polycation chains on surfaces.29 The ferrocyanide ions in these multilayer films can, however, be replaced by PGA through an ion exchange process, whereas they remain in the film when it is brought into contact with a HA solution. This is due to the fact that PGA chains can diffuse into the film whereas HA cannot. Exchange processes in polyelectrolyte multilayers were also reported recently by Kharlampieva and Sukhishvili in films where the polyanion and the polycation are held together by hydrogen bonds.30 These authors found, in a given pH range, a gradual replacement of chains held by hydrogen bonding by chains interacting through electrostatic forces. It is the aim of the present study to further investigate how exponentially growing films behave when brought into contact with multilvalent ions (small ions or polyelectrolyte chains). We investigate here two exponentially growing films: HA-PLL and HA-PAH multilayers. We use ferrocyanide and ferricyanide ions as small ion probes. These ions are used as model probes because of their high charge density and their electrochemical properties, which allow measurement of their permeation through the whole film thickness by means of electrochemical techniques such as cyclic voltammetry. The study will be performed by means of a quartz crystal microbalance with dissipation (QCM-D), by surface plasmon resonance (SPR) spectroscopy coupled with cyclic voltammetry, and by Fourier (20) Elbert, D. L.; Herbert, C. B.; Hubbell, J. A. Langmuir 1999, 15, 5355. (21) Picart, C.; Lavalle, Ph.; Hubert, P.; Cuisinier, F. J. G.; Decher, G.; Schaaf, P.; Voegel, J. C. Langmuir 2001, 17, 7414. (22) Picart, C.; Mutterer, J.; Richert, L.; Luo, Y.; Prestwich, G. D.; Schaaf, P.; Voegel, J. C.; Lavalle, Ph. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 12531. (23) Lavalle, Ph.; Gergely, C.; Cuisinier, F. J. G.; Decher, G.; Schaaf, P.; Voegel, J. C.; Picart, C. Macromolecules 2002, 35, 4458. (24) Boulmedais, F.; Ball, V.; Schwinte, P.; Frisch, B.; Schaaf, P.; Voegel, J. C. Langmuir 2003, 19, 440. (25) Debreczeny, M.; Ball, V.; Boulmedais, F.; Szalontai, B.; Voegel, J. C.; Schaaf, P. J. Phys. Chem. B 2003, 107, 12734. (26) Izumrudov, V. A. Ber. Bunsen-Ges. Phys. Chem. 1996, 100, 1017. (27) Boulmedais, F.; Bozonnet, M.; Schwinte, P.; Voegel, J.-C.; Schaaf, P. Langmuir 2003, 19, 9873. (28) Hu¨bsch, E.; Fleith, G.; Fatisson, J.; Labbe´, P.; Voegel, J.-C.; Schaaf, P.; Ball, V. Langmuir 2005, 21, 3664. (29) Kiriy, A.; Gorodyska, G.; Minko, S.; Tsitsilianis, C.; Jaeger, W.; Stamm, M. J. Am. Chem. Soc. 2003, 125, 11202. (30) Kharlampieva, E.; Sukhishvili, S. A. Langmuir 2004, 20, 10712.

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transform infrared spectroscopy in the attenuated total reflection mode (FTIR-ATR). As we will see, whereas the films remain stable in the presence of ferricyanide ions, they are partially dissolved in the presence of ferrocyanide ions, the dissolution process being much more rapid for the (HA-PLL)n films than for the (HA-PAH)n films. This suggests a stronger interaction between HA and PAH than between HA and PLL. This stronger interaction will be confirmed by exchange experiments, and it will be shown that (HA-PLL)n films can be entirely converted into HAPAH-containing films by the simple contact of the (HAPLL)n multilayer with a PAH solution, PLL being quantitatively exchanged with PAH chains. The exchange of PAH chains in (HA-PAH)n multilayers with PLL, on the other hand, does not take place. Materials and Methods Chemicals. All the polyelectrolyte multilayers were built from 10 mM Tris buffer (tris(hydroxymethyl)aminomethane; Gibco BRL) at pH 7.4 in the presence of either 150 or 15 mM NaCl (Prolabo France). The pH of this Tris-NaCl buffer was adjusted with concentrated hydrochloric acid. All the solutions were made from ultrapure water (Milli-Q, Millipore, F ) 18.2 MΩ‚cm). The ferrocyanide solutions (K4Fe(CN)6‚2H2O, CAS 14459-95-1, Sigma, P9383, batch 033K0128) were prepared in the same Tris-NaCl buffer with the concentration changing from 0.2 to 2 mM. Ferricyanide (Merck) was dissolved in the Tris-NaCl buffer at a concentration of 1 mM. The polyelectrolytes used for the multilayer buildups were poly(ethylenimine) (PEI; Polysciences, 30% w/w solution, Mw ) 30000 g/mol), HA (Bioiberica, Mw ) 400000 g/mol), poly-L-lysine hydrobromide (Sigma, P-2636, lot 031K5100, viscosimetric molecular weight 48100 g/mol, molecular weight determined by multiangle light scattering 39000 g/mol), and poly(allylamine hydrocholoride) (Aldrich, cat. 28,322-3, lot 05212MO-232, molecular weight 65000-70000 g/mol). For the multilayer films used in SPR and cyclic voltammetry experiments, the PEI concentration was equal to 1 mg‚mL-1 whereas the HA and PLL concentrations in the Tris-NaCl buffer were equal to 0.2 mg‚mL-1. For the QCM-D experiments, all the polyelectrolytes were adsorbed from 1 mg‚mL-1 solutions in the presence of TrisNaCl buffer. The reason for this change in concentration is that the SPR spectroscopy-cyclic voltammetry cell has an internal volume of 4.5 mL, implying a huge consumption of polyelectrolytes. By means of a QCM-D, it was checked that this change in polyelectrolyte concentration has no significant effect on the LBL construction provided the durations of the deposition steps are long enough (data not shown). The minimal adsorption duration to reach steady-state frequency changes in this QCM-D experiment performed at 0.2 mg‚mL-1 was 3 min for all the used polyelectrolytes. The polyelectrolyte solutions were prepared a few hours before the beginning of the LBL deposition to allow the highly hydrated hyaluronic acid to totally dissolve in the buffer. Multilayer Buildup. In SPR spectroscopy, cyclic voltammetry (CV), and the QCM-D experiment, the multilayers were built on gold-coated LASF9 glass and quartz coated with a SiO2 layer, respectively. Cyclic voltammetry was performed on the same substrates as the SPR experiments and in the same measurement cell. The glass substrates used for the SPR experiments were cleaned with a 2% (v/v) Hellmanex solution (Hellma GMBH, Mu¨llheim, Germany) in an ultrasonic bath for 10 min. They were then rinsed with distilled water and ethanol and dried under a stream of nitrogen before being coated with 2 nm of chromium and 50 nm of gold (Edwards FL 400 vacuum evaporator). They were then stored in a controlled atmosphere before use for the LBL deposition. Before deposition of the polyelectrolyte multilayer, the chromium-gold-coated glass slides were cleaned again with a 2% (v/v) Hellmanex solution, distilled water, a 1 M hydrochloric acid solution, distilled water again, and finally the Tris-NaCl buffer. First, PEI was deposited for 10 min (5 min for the QCM-D experiment), followed by an extensive rinse with buffer. Then repeated cycles of HA adsorption for 10 min (5 min for the QCM-D

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experiment), a buffer rinse for 10 min, adsorption of PLL or PAH for 10 min (5 min for the QCM-D experiment), and a buffer rinse were performed up to the deposition of PEI-(HA-PLL)4-HA, PEI-(HA-PLL)7-HA, and PEI-(HA-PAH)7-HA multilayers. SPR and CV Measurements. Surface plasmon resonance spectroscopy relies on the collective electron excitation upon the irradiation with an electromagnetic wave having an appropriate component of the wave vector in the plane of the noble metal/ dielectric interface. This excitation manifests itself in a reduction of the reflected light intensity if the angle of incidence is changed, as described elsewhere.31 The surface plasmon coupling angle is highly sensitive to refractive index changes at the surface and can therefore be used to monitor even minor surface adsorption/ desorption events. The most common Kretschmann configuration32 where a gold-coated glass slide is coupled to the base of a prism by means of an index matching oil was used to perform SPR spectroscopy in this study. The cyclic voltammetry experiments were recorded by using a conventional three-electrode setup, where the gold layer of the substrate also used for the SPR experiment served as the working electrode, the reference electrode being a Ag/AgCl/KCl(sat) electrode and the auxiliary electrode being a platinum wire. The electrochemical measurements were performed by means of a model 263A potentiostat/galvanostat (EG&G Princeton Applied Research) driven by Corrware 2.0 software (Scribner Associates). Voltammograms were recorded from -0.2 to +0.5 V, all potentials being measured against the Ag/AgCl/KCl(sat) reference electrode. These CV experiments were performed at different steps of the experiments. (1) Directly at the end of the buildup of the polyelectrolyte multilayer in the absence of redox probes and at a scan rate of 100 mV‚s-1. Indeed, scan rates between 10 and 500 mV‚s-1 are rather typical in cyclic voltammetry experiments.33 (2) At different time intervals after the introduction of ferrocyanide or ferricyanide solutions (concentrations varying between 0.2 and 2 mM in the Tris-NaCl buffer) which were injected into the cell at a flow rate of 2.65 cm3‚h-1 for 10 min and then at 0.51 cm3‚h-1 for longer injection times. The flow rate was changed to reduce the consumption of ferrocyanide solution owing to the huge volume of the measuring cell (4.5 mL). These experiments were also done at a given scan rate of 100 mV‚s-1 to measure the permeation of the electroactive species into the LBL assembly. QCM-D Experiments. The QCM-D experiments were performed as described in previous publications24,25 with the Q300 microbalance from Q-sense (Q-Sense-AB, Go¨teborg, Sweden). It has already been shown that polyelectrolyte multilayers can be deposited directly onto gold by adsorbing first a PEI layer instead of a positively charged self-assembled monolayer as is usually done by other authors.34,35 Moreover, the frequency changes were measured at the fundamental frequency of the crystal (close to 5 MHz) as well as at the third, fifth, and seventh harmonics close to 15, 25, and 35 MHz, respectively. This, as well as the dissipation changes, related to the loss of energy from the crystal in the solution and in the adsorbed film, allows in principle calculation of the shear modulus and the shear viscosity of the LBL films.36,37 In particular, in the case of high dissipation and in the absence of an overlap of the normalized frequency changes, (∆fυ/υ, where υ is the overtone number), the Sauerbrey relationship,38 giving direct access to the adsorbed mass per unit area from the measured frequency changes, cannot be applied. The multilayers were deposited onto commercial SiO2-coated quartz crystals from Q-Sense. (31) Knoll, W. Annu. Rev. Phys. Chem. 1998, 49, 569. (32) Kretschmann, E.; Raether, H. Z. Naturforsch., A 1968, 23, 2135. (33) Bard, A. J.; Faulkner, L. R. Electrochemical methods; J. Wiley: New York, 1980. (34) (a) Tian, S.; Liu, J.; Zhu, T.; Knoll, W. Chem. Commun. 2003, 2738. (b) Tian, S.; Baba, A.; Liu, J.; Wang, Z.; Knoll, W.; Park, M.-K.; Advincula, R. Adv. Funct. Mater. 2003, 13, 473. (35) Ferreyra, N.; Coche-Guerente, L.; Fatisson, J.; Teijelo, M. L.; Labbe, P. Chem. Commun. 2003, 2056. (36) Rodahl, M.; Kasemo, B. Sens. Actuators, A 1996, 54, 448. (37) Voinova, M. V.; Rodahl, M.; Jonson, M.; Kasemo, B. Phys. Scr. 1999, 59, 391. (38) Sauerbrey, G. Z. Phys. 1959, 155, 206.

Ball et al. FTIR-ATR Spectroscopy. The FTIR-ATR spectroscopy experiments were performed on an IFS 55 spectrometer (Bruker, Wissembourg, France). The following of the multilayer buildup by ATR-FTIR spectroscopy has been extensively described in our previous papers25,27 and will be only briefly summarized here. The polyelectrolyte multilayers, either PEI-(HA-PLL)6 or PEI(HA-PAH)6, were prepared by injecting the polycation, buffer, polyanion, and buffer solutions over the surface of a trapezoidal ZnSe crystal which was cleaned with Hellmanex [2% (v/v)] and ethanol before multilayer deposition. For these experiments, the buffer was prepared from D2O instead of H2O because the amide I band of the polypeptides (between 1600 and 1700 cm-1) is strongly affected by the strong absorption of water around 1643 cm-1 (O-H bending mode) whereas the corresponding vibration in D2O is around 1209 cm-1. The construction of the multilayer was followed by recording infrared spectra from 512 scans between 700 and 4000 cm-1, with a resolution of 2 cm-1 during each buffer rinse step. The spectrum of the PEI layer was subtracted from each of these spectra to follow the multilayer buildup. After the buildup of six bilayers, the PEI-(HA-PLL)6 and PEI-(HA-PAH)6 films were put into contact with a PAHand PLL-containing solution, respectively. These solutions had a concentration of 1 mg‚mL-1. The infrared spectra were then recorded by summing over 128 scans to improve the time resolution of the exchange kinetics. All these spectra were compared with the spectrum of the initial PEI layer. When the exchange kinetics reached a steady state, the multilayer was rinsed with pure buffer and a 512 scan spectrum was recorded to obtain the infrared spectrum of the film in its final state without any contribution from solubilized polyelectrolytes. Ellipsometry. To evaluate the effect of the exposure of the PEI-(HA-PLL)4-HA multilayer to the ferrocyanide solution, the film was built up by dipping a silicium wafer (WaferNet Gmbh, Germany), covered with an about 2 nm thick silicium oxide layer, alternatively in the polycation, buffer, polyanion, and buffer solutions. The silicium wafer was cleaned within an ethanol bath, in a Hellmanex (2% w/w) bath at 60 °C for 10 min, rinsed with distilled water, put in 0.1 M hydrochloric acid for 10 min at 60 °C, and subsequently rinsed with water and TrisNaCl buffer. Each dipping step lasted over 10 min. Finally, after its buildup the film was rinsed with distilled water, to avoid sodium chloride deposition upon drying, and dried under a stream of nitrogen, and its thickness was measured ellipsometrically (Jobin Yvon, model PZ 2000) at a wavelength of 632.8 nm and at an incident angle of 45°. The ellipsometric angles were transformed in thickness using an optical model in which the thin silicium oxide and the polyelectrolyte multilayer were considered as a unique layer with a refactive index of 1.465. This is justified by the fact that the polyelectrolyte multilayers usually have refractive indexes close to 1.4-1.5 as obtained from OWLS experiments.21-23

Results and Discussion Interactions of Ferrocyanide and Ferricyanide Ions with HA-PLL and HA-PAH Multilayers. We first checked the possibility to build PEI-(HA-PLL)n and PEI-(HA-PAH)n multilayers on a bare gold surface by a QCM-D experiment. Parts a and b of Figure 1 represent the normalized frequency shifts of the third and seventh overtones (15 and 35 MHz, respectively) during the HAPLL and HA-PAH buildup processes. All the films were deposited onto a PEI precursor layer. The normalized frequencies evolve for both films in a superlinear way with the number of deposited layers. One can point out that the normalized frequency shifts of the different overtones (only the third and seventh are represented in this figure) do not overlap. This is a characteristic signature of a viscoelastic behavior of the films and is corroborated by an important increase of the dissipation losses measured during the film buildup processes (data not shown). It thus excludes the use of the Sauerbrey equation to evaluate quantitatively the mass of polyelectrolyte deposited per unit area of the multilayer.

Multivalent Ion-Growing Multilayer Interactions

Langmuir, Vol. 21, No. 18, 2005 8529 Table 1. Thickness of a PEI-(HA-PLL)n Multilayer Constructed from a Tris-150 mM NaCl Solution As Measured by an Ellipsometer in the Dry State and after Its Exposure to a 1 mM Ferrocyanide Solution investigated architecture

thickness ( σa/nm

SiO2 SiO2-PEI-(HA-PLL)2 SiO2-PEI-(HA-PLL)4-HA SiO2-PEI-(HA-PLL)4-HA + contact with Fe(CN)64-, water rinse, and drying with nitrogen

2.8 ( 0.1 30.1 ( 2.5 47.1 ( 5.3 32.6 ( 5.3

a The average thickness and standard deviation are obtained from five measurements on different locations of the silicium oxide layer or on the surface of the polyelectrolyte film.

Figure 1. (a) Evolution of the normalized frequency changes at 15 MHz (0) and at 35 MHz (s) measured with the QCM-D during the buildup of a PEI-(HA-PLL)4-HA multilayer on a SiO2-coated quartz crystal from a Tris-15 mM NaCl buffer at pH 7.4. For the sake of clarity, the reduced frequency changes at 5 and 25 MHz are not represented. The beginning of each polyelectrolyte injection is labeled by a “C” for PLL and by an “A” for HA. The time at which the injection of Fe(CN)64- (at a concentration of 1 mM in the Tris-15 mM NaCl buffer) began is also indicated. (b) Same as in (a) but for a PEI-(HA-PAH)4HA multilayer. In both panels, the horizontal dashed line corresponds to the signal reached at the end of the exposure to the ferrocyanide solution before further exposure to the buffer solution.

Once the films were built, they were brought into contact with a 1 mM ferrocyanide solution (10 mM Tris, 15 mM NaCl buffer). Unexpectedly, for both films a strong decrease in the normalized frequency changes was observed (Figure 1). At the same time the dissipations decreased (data not shown). Both the frequency and the dissipation changes leveled off at values close to those corresponding, respectively, to PEI-(HA-PLL)2-HA and PEI-(HA-PAH)3 films (see the horizontal lines in Figure 1). Parts a and b of Figure 1 correspond to films made of 4.5 bilayers in contact with the ferrocyanide solutions. Similar results and in particular similar values of the normalized frequency shifts after contact with the Fe(CN)64- ions were obtained on films made of seven bilayers. This suggests that PEI-(HA-PLL)n and PEI(HA-PAH)n multilayers are not homogeneous all over the film but that the polyanion/polycation interactions are stronger close to the solid surface (or to the PEI starting

layer) over a thickness extending approximately over two to three bilayers. This is probably due to the stronger interactions between the first deposited polyelectrolytes and the substrate than between the polyelectrolytes adsorbed in a later stage and the polyelectrolytes adsorbed in the previous stages of the buildup process. The observed decrease in frequency change could also be due to an effect other than the partial dissolution of the film. One could imagine that a strong water and chloride ion release could occur upon exposure of the PEI-(HAPLL)4-HA and PEI-(HA-PAH)4-HA architectures to the ferrocyanide-containing solution. To confirm or to discard this assumption, we performed an additional experiment in which a PEI-(HA-PLL)4-HA multilayer deposited onto an oxidized silicium wafer was put into contact with a ferrocyanide solution at 1 mM for 1 min. The layer thickness, proportional to its optical mass, was measured after water rinse and nitrogen drying, before and after exposure to the ferrocyanide solution. The results are gathered in Table 1, and it appears that the contact with the ferrocyanide ions induces a reduction in the optical mass of the film. The optical mass reached after the contact with ferrocyanide is very close to the thickness of a PEI-(HA-PLL)2 film. Hence, the experiment performed with ellipsometry is in full aggreement with that done with a QCM-D and confirms that, upon contact with Fe(CN)64- anions, the film partially dissolves. To verify if the film stability depends on the ionic strength of the polyelectrolyte solutions used during the film buildup, similar experiments were performed on PEI(HA-PLL)n films constructed with polyelectrolyte solutions containing 150 mM NaCl. After contact with a 1 mM ferrocyanide solution the normalized frequency changes decreased again up to their values reached roughly after the deposition of PEI-(HA-PLL)-HA (see Figure 1 of the Supporting Information). The zone of the multilayer that is more stable is thus more reduced for films constructed from polyelectrolyte solutions of higher ionic strength (1.5 bilayers for a film built from 150 mM NaCl compared to 2.5 bilayers for films constructed from 15 mM NaCl solutions). This is expected since films constructed from solutions of high ionic strength are more extended, the polyelectrolytes constituting the films being in a more loopy conformation. Hence, the interactions between the polyanions and the polycations are less tight at high ionic strength.39 We also checked the influence of the concentration of the ferrocyanide ion concentration on the dissolution of PEI-(HA-PLL)n films by varying the Fe(CN)64- concentration from 0.2 to 2 mM in Tris150 mM NaCl buffer. The dissolution rate as measured by the normalized frequency shift per unit time increased steadily with increasing Fe(CN)64- ion concentration (data (39) Kovacevic, D.; van der Burgh, S.; de Keizer, A.; Cohen Stuart, M. A. J. Phys. Chem. B 2003, 107, 7998.

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not shown), but the level of frequency change at the steady state is almost independent of the ferrocyanide concentration in the investigated experimental range. These results have to be compared with those obtained recently, where another exponentially growing film, namely, PEI-(PGA-PAH)n, was brought into contact with ferrocyanide solutions.28 No dissolution took place, but the ferrocyanide ions diffused into the films as observed by cyclic voltammetry and ATR-FTIR spectroscopy. This indicates that the interactions between PGA and PAH are stronger than those between HA and PAH when probed by ferrocyanide ions. The reason for this different behavior is not clear but could originate from the higher persistence length of HA compared to PGA that disfavors close multiple contacts of the polyanion with the PAH chains. The disruption of the HA-PLL and HA-PAH interactions by the incoming ferrocyanide anions can probably be related to the charge density of the ferrocyanide anions. If ions of lower charge density would interact with these multilayers, one would expect a smaller disruption probability of the established electrostatic bridges, ensuring the stability of the multilayers. The ferricyanide ions exhibit three negative charges but have the same structure as the ferrocyanide ions and hence about the same radius (with some small differences however owing to differences in their hydration states). We thus investigated the interactions of Fe(CN)63-, instead of Fe(CN)64-, with HAPLL films. The films investigated were terminated by HA. In marked contrast to the effect of Fe(CN)64- ions, almost no signal changes were observed by SPR spectroscopy (see Figure 2 of the Supporting Information) and by a QCM-D experiment (data not shown) when the polyelectrolyte films are put into contact with Fe(CN)63- anions. This indicates that the HA-PLL multilayers remain stable in the presence of ferricyanide ions. It has to be noted that these experiments were performed on a PEI-(HA-PLL)7HA multilayer film and on a PEI-(HA-PLL)4-HA architecture and that the result was the same, namely, that no appreciable frequency change (less than 10 Hz) could be detected upon the contact with the ferricyanidecontaining solution. The reason we did these experiments on PEI-(HA-PLL)7-HA films rather than on PEI-(HAPLL)4-HA films is due to the fact that the latter ones do not totally cover the surface whereas the former ones ensure a full substrate coverage with no pores going from the top of the film down to the substrate.21 Cyclic voltammetry coupled with SPR shows a strong increase of the oxidation and reduction peaks of Fe(CN)64and Fe(CN)63-, respectively, when the multilayer film is put into contact with a ferrocyanide solution (see Figure 2). Ferricyanide ions are thus present in the film, close to the gold electrode, the Fe(CN)64- ions being formed during the reduction of Fe(CN)63-. When the ferricynanide ion solution is rinsed by pure buffer, no change in the electrochemical signal is observed, indicating that the ferricyanide ions remain in the film. A similar effect was observed previously for the ferrocyanide ions present in PGA-PAH multilayers.28 These multivalent ions, once present in the film, are thus almost trapped inside the multilayer. One could expect that, upon reduction of ferricyanide into ferrocyanide and a concomitant increase in the charge density of the electroactive species, a film dissolution should occur as is observed when the multilayer film is put into direct contact with a ferrocyanide solution. However, this is not observed, which can be rationalized since the amount of produced ferrocyanide is very small and this ferrocyanide is produced close to the gold electrode, hence in the region of the film that is not

Ball et al.

Figure 2. Cyclic voltammetry experiments of Fe(CN)63obtained at a scan rate of 100 mV‚s-1 on a PEI-(HA-PLL)7HA8 polyelectrolyte multilayer built up in the presence of Tris (10 mM) with 150 mM NaCl and subsequently put into contact with a 1 mM Fe(CN)63- solution (curve 1). The film was then intensively rinsed with buffer for 3 h, leading to less than 10% reduction in the oxidation and reduction currents (data not shown), before being put into contact with hyaluronic acid solution for 50 min (curve 2). It was then put into contact with buffer for 10 min (data not shown) and finally with the PLL solution for 5 min (curve 3).

subjected to dissolution upon contact with ferrocyanide ions. Moreover, the produced ferrocyanide is oxidized again in ferricyanide during the potential scan in the anodic direction. We also emphasize that the ferricyanide release induced by PLL adsorption on a film ending with HA cannot be directly compared with the results obtained in ref 28 in which we studied the ferrocyanide release from PEI(PGA-PAH)10 and PEI-(PGA-PAH)10-PGA films when they were, respectively, put into contact with PAH and PGA, hence with polyelectrolytes of the same sign as the last deposited polyelectrolyte. Exchange Processes. Previously we found that ferrocyanide ions present in a PGA-PAH multilayer can be removed from the film when it is brought into contact with a PGA solution.28 On the other hand, when the film is brought into contact with hyaluronic acid, another polyanion, no ferrocyanide ion release from the film takes place. These observations were interpreted by the fact that PGA can diffuse into a PGA-PAH film (it diffuses “in” and “out” of the film in each deposition step during the film buildup) whereas HA does not diffuse into the multilayers. We believe that the absence of HA diffusion into HA-PLL as well as in PGA-PAH multilayers is related to its high persistence length. The ferrocyanide ion release is then due to an exchange process between the Fe(CN)64- ions from the film and the PGA chains from the solution. A similar effect should thus take place for our systems. If this interpretation is correct, no ferricyanide release should be observed when a PEI-(HA-PLL)7HA8 multilayer loaded with ferricyanide ions is exposed to an HA solution, since HA is known not to diffuse into such multilayers.22 This is indeed observed by cyclic voltammetry (Figure 2). This validates the exchange hypothesis of multivalent ions present in a film by polyelectrolytes of the same sign that can diffuse into the multilayer. One also observes that when an HA-PLL film, loaded with ferricyanide, is exposed to a PLL solution, a very fast decrease in the oxidation and reduction peaks is observed (Figure 2). This reduction of the current is

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indicating that PAH is not exchanged with the PLL chains present in the solution. The occurrence of an exchange of PLL with PAH whereas the reverse process does not take place is a strong indication that PLL interacts less strongly with HA than PAH and validates the assumption we made to explain the differences in dissolution kinetics of PEI(HA-PLL)n and PEI-(HA-PAH)n multilayers induced by the presence of Fe(CN)64- ions in solution. Conclusion

Figure 3. ATR-FTIR spectra of a PEI-(HA-PLL)6 multilayer film (b), of a PEI-(HA-PAH)6 multilayer film (4), and of a PEI-(HA-PLL)6 multilayer film after 16 h of contact with a PAH solution (9) at 1 mg‚mL-1 in a Tris-150 mM NaCl buffer. The spectrum indicated by “4” was then adjusted to the spectrum indicated by “9” by a simple multiplication factor. The obtained adjustment is shown as the spectrum indicated by “]”. The curve indicated by “O” represents the difference between the measured spectrum after exchange with PAH (9) and the calculated spectrum.

associated with a ferricyanide release from the multilayer similarly to the way the ferrocyanide ions were released from a PGA-PAH film in contact with a PGA solution.28 Exchange processes in multilayers not only take place between small ions and polyelectrolyte chains but can also take place between polyelectrolyte chains from the film and from the solution. A closer look at Figure 1 reveals that it takes more than 15 min for the HA-PAH to partially dissolve in the presence of 1 mM ferrocyanide ions whereas only 2-3 min is sufficient in the case of the HA-PLL architecture at a given ionic strength of 15 mM. This suggests a stronger interaction between HA and PAH than between HA and PLL. Such differences in the interactions should have a strong influence on the exchange behavior of these polyanions. To analyze this aspect, we followed the buildup of a PEI-(HA-PLL)6 film by means of ATR-FTIR spectroscopy on films deposited on a ZnSe crystal. Such a film displayed a well-defined amide I band between 1600 and 1700 cm-1 (Figure 3). When this film is brought into contact with a PAH solution (1 mg‚mL-1 in a Tris-150 mM NaCl buffer) for 16 h, the amide I band totally disappears and the spectrum becomes identical to that of an HA-PAH multilayer. This was verified quantitatively by adjusting the infrared spectrum of a PEI-(HA-PAH)6 film to that corresponding to the PEI-(HA-PLL)6 film brought into contact with the PAH solution for 16 h. The difference spectrum between the experimental and fitted spectrum is in the level of the experimental noise in the whole region of the fit (between 1500 and 1700 cm-1) as shown at the bottom of Figure 3. This clearly indicates that the PLL chains constituting the film were quantitatively exchanged with PAH chains from the solution, modifying the PEI-(HA-PLL)6 film into a multilayer containing only HA and PAH. However, the infrared signal obtained after the exchange process is lower than that obtained for a PEI-(HA-PAH)6 multilayer built up by a layer by layer process. Nevertheless, the spectrum obtained after the exchange process can be obtained from the spectrum of the PEI-(HA-PAH)6 film by a single multiplication factor as shown in Figure 3. On the other hand, when a PEI-(HA-PAH)6 film is brought into contact with a PLL solution (1 mg‚mL-1 in a Tris-150 mM NaCl buffer), no change in the IR spectra is observed (see Figure 3 of the Supporting Information),

We have investigated the interactions between multivalent ions (small ions or polyelectrolytes) and two exponentially growing polyelectrolyte multilayers, namely, (HA-PLL)n and (HA-PAH)n films. We used ferrocyanide and ferricyanide ions as small ion probes. The most striking observation is that, even though these two ions only differ by one charge unit, the ferrocyanide ions induce the partial dissolution of both multilayers whereas both films remain stable in the presence of ferricyanide ions. The dissolution process of (HA-PLL)n films is more rapid than that of (HA-PAH)n films, indicating a stronger interaction between HA and PAH compared to HA and PLL. This is confirmed by exchange experiments. It is shown that when an (HA-PLL)n multilayer is put into contact with a PAH solution, PLL is quantitatively exchanged with the PAH chains and transformed into an HA- and PAH-containing film, whereas an (HA-PAH)n multilayer remains stable in the presence of a PLL solution. This work enters also into the recent trend to prepare polyelectrolyte multilayers which can be eroded or dissolved by the application of an external stimulus.40-43 Such multilayers may have important applications for sustained drug release. Until now the film erosion could only be induced by changes in the external pH or ionic strength. This work shows that multivalent ions can also trigger such a dissolution effect on certain multilayered films for which the interaction strength between the polyanions and the polycations seems to be rather weak. This work also stimulates a deep study on polyelectrolyte-polyelectrolyte exchange dynamics on such kinds of multilayer films. The kinetics of such exchange processes may certainly depend on the nature of the used polycations and polyanions, on their average degre of polymerization, on the degree of ionization if weak polyelectrolytes are used, on the ionic strength of the solution, and on the temperature. Furthermore, the complexation process between HA and PLL on the one side and between HA and PAH in solution will be described in a subsequent study to better understand the difference in their respective interactions inside polyelectrolyte multilayers. Acknowledgment. This work was supported by the program ACI “Nanosciences” (Grant NR204) from the Ministe`re Franc¸ ais De´le´gue´ a` la Recherche. Supporting Information Available: Evolution of normal frequency changes and the surface plasmon coupling angle and ATR-FTIR spectra of a PEI-(HA-PAH)6 multilayer. This material is available free of charge via the Internet at http://pubs.acs.org. LA050866O (40) . (a) Sukhishvili, S. A.; Granick, S. J. Am. Chem. Soc. 2000, 122, 9550. (b) Sukhishvili, S. A.; Granick, S. Macromolecules 2002, 35, 301. (41) Cho, J.; Caruso, F. Macromolecules 2003, 36, 2845. (42) Dubas, S. T.; Schlenoff, J. B. Macromolecules 2001, 34, 3736. (43) Vazquez, E.; Dewitt, D. M.; Hammond, P. T.; Lynn, D. M. J. Am. Chem. Soc. 2002, 124, 13992.