Laser processing of polyethylene glycol derivative

Applied Surface Science 255 (2009) 5605–5610

Contents lists available at ScienceDirect

Applied Surface Science journal homepage: www.elsevier.com/locate/apsusc

Laser processing of polyethylene glycol derivative and block copolymer thin films R. Cristescu a,*, C. Popescu a, A.C. Popescu a, S. Grigorescu a, L. Duta a, I.N. Mihailescu a, A. Andronie b, I. Stamatin b, O.S. Ionescu c, D. Mihaiescu c, T. Buruiana d, D.B. Chrisey e a

National Institute for Laser, Plasma and Radiation Physics, MG-36, RO-77125, Bucharest, Romania University of Bucharest, 3Nano-SAE Research Center, P.O. Box MG-11, Bucharest-Magurele, Romania c University of Agriculture Sciences and Veterinary Medicine, 59 Marasti, Bucharest, Romania d Petru Poni Institute of Macromolecular Chemistry, Aleea Grigore Ghica Voda, 41A, Iasi, Romania e Rensselaer Polytechnic Institute, Department of Material Science, 110 8th Street, Troy, NY 12180-3590, USA b

A R T I C L E I N F O

A B S T R A C T

Article history:

We report the deposition by MAPLE of: (i) a novel polyethylene glycol derivative with carboxyl functional groups and (ii) a block copolymer: poly(ethylene glycol)methyl ether-block-poly(caprolactone)-blockpoly(ethylene glycol)methyl ether. We used a KrF* excimer laser source (l = 248 nm, t = 25 ns, n = 5 Hz). The laser fluence was set within the 200–700 mJ/cm2 range. The deposited thin films have been investigated by FTIR and AFM. We have concluded that the main functional groups of starting materials are present in the transferred film. We also examined the influence of laser fluence on both thin film structure and morphology. ß 2008 Elsevier B.V. All rights reserved.

Available online 4 October 2008 Keywords: Controlled drug release Porous polymers Thin films Matrix assisted pulsed laser evaporation

1. Introduction Increasing attention has been focused recently on methods of giving drugs continually for prolonged time periods and in a controlled fashion [1]. The primary method of accomplishing this controlled release has been through incorporating the drug within biodegradable biopolymers. To address these needs, a novel approach of developing drug delivery strategy from the perspective of biopolymer-drug compatibility and interactions at the molecular levels based on matrix-assisted pulsed laser evaporation (MAPLE), has emerged [2,3]. The method relies on the finding that the biopolymers dissolved within a frozen, absorbing solvent can, upon laser irradiation, eject in the gas phase in intact and functional form [4]. Past work has clearly demonstrated the potential of MAPLE for the deposition of a wide range of organic macromolecules (e.g. carbohydrates [5], nanotubes [6]), polymers/ biopolymers (e.g. polyethylene glycol [4], polylactide-co-glicolide [7]) or even of larger biological structures (e.g., viruses, proteins, cells, and tissue components). Recently, thin films of polysaccharides [8–10], blood and mussel proteins [11–13] as well as collagen [14] were successfully produced for drug delivery and diagnostic

* Corresponding author. Tel.: +40 21 4574491; fax: +40 21 4574243. E-mail addresses: rodica.cristescu@inflpr.ro, [email protected] (R. Cristescu). 0169-4332/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.apsusc.2008.09.060

applications. We used in these MAPLE experiments: (i) a novel polyethylene glycol derivative with carboxyl functional groups (symbol PEG 1) and (ii) a block copolymer: poly(ethylene glycol)methyl ether-block-poly(caprolactone)-block-poly(ethylene glycol)methyl ether (symbol PEG 4). The goal of this work is to explore laser processing of these materials because of their compatibility with drugs, proteins, peptides and amino acids to create suitable constructs for drug delivery applications. 2. Materials and methods 2.1. Materials We used as raw material the pure commercial polyethylene glycol. To produce suitable MAPLE target matrices, PEG 1 and PEG 4 were solvated into a 2% solution with dimethyl sulfoxide (DMSO) and chloroform, respectively. 2.1.1. PEG 1 PEG 1 has been obtained using a reaction between pure polyethylene glycol (Mn = 8000) and maleic anhydride (1:2 molar ratio) in the medium of 1,4-dioxane and pyridine as catalyst. After the solvent was distilled off in vacuum, the resulting product was dissolved in methylene chloride and then washed with water. The expected derivative was collected by separation and removing solvent. The length of hydrophilic sequence is n = 181.4. This PEG

5606

R. Cristescu et al. / Applied Surface Science 255 (2009) 5605–5610

laser spot area was 7–8 mm2. The number of subsequent laser pulses applied for the deposition of one film was 15,000. In all experiments both sides polished Si substrates were used. Depositions have been performed in N2 at a dynamic equilibrium pressure within 40–400 Pa range. A control set of films was prepared by drop casting in order to provide a control sample. Fig. 1. The chemical structure of polyethylene glycol derivative with carboxyl functional groups (PEG 1).

derivative is soluble in methylene chloride, dioxane, methyl/ethyl alcohol, tetrahydrofurane (THF) and DMSO. The chemical structure of PEG 1 is shown in Fig. 1. 2.1.2. PEG 4 The ternary copolymer synthesis by the interaction between two oligomers with functional groups. This first implied the synthesis of oligomeric monomethyl ether derivative with a final carboxyl group (I-1) by a chemical reaction between the hydroxyl group of monofunctional oligomer (Mn = 750) with the succinic anhydride placed in both methylene chloride and piridine environments. The structure of this intermediary is given in Fig. 2a. Further, the aformentioned carboxylate derivative reacted with polycaprolactone diol (average Mn = 2000) using a molar ratio of 2:1. The reaction was conducted in the presence of dichlorcarbodiimide that serves like a reactant in the fixation of water. The structure of the ternary copolymer that contains two polyethylene glycol blocks and one polycaprolactone block (symbol PEG 4) is visible in Fig. 2b.

2.2.2. PEG 4 During deposition the double face polished single crystalline Si substrate was kept at room temperature. The targetsubstrate distance was 4 cm. The laser energy per pulse was kept constant of 46 mJ. The incident laser fluence was stabilized at values slightly exceeding the ablation threshold fluence of 190 mJ/ cm2. For deposition of one film we applied 20,000 subsequent pulses. The irradiation spot area was within the range of 9– 23 mm2. Depositions have been performed at a residual pressure of 5.3–6.6 Pa. 2.3. Characterization methods All thin films were characterized by Fourier transform infrared spectroscopy (FTIR), and atomic force microscopy (AFM). FTIR spectra of PEG 1 thin films were recorded with a Jasco 6,200 (8 cm 1 resolution) equipped with a specular reflectance device with varied angle VeeMax II, while those corresponding to PEG 4 were performed with a Nexus 470 apparatus (Thermo Nicolet Corporation, Madison, WI, USA) with 4 cm 1 resolution. AFM micrographs were recorded with an Integrated Platform SPM – NTegra model Prima in semicontact mode, error mode and phase contrast.

2.2. Experimental conditions 3. Results and discussion MAPLE depositions of PEG 1 derivative and PEG 4 block copolymer were performed using a pulsed excimer KrF* laser (l = 248 nm, tFWHM = 25 ns, n = 5 Hz). The laser beam was incident on target surface at 458. Prior to deposition, 5 ml of the solvated fluid was pipetted into the target holder and frozen by immersing in liquid nitrogen (LN). The copper target holder was maintained at a temperature of 173 K. The target was rotated at a rate of 0.4 Hz during film deposition to avoid heating and possible drilling. Prior to the introduction in the chamber, the substrates were cleaned with ethanol and acetone for 10 min in an ultrasonic bath. 2.2.1. PEG 1 The target-substrate distance was 3 cm. After preliminary tests, we set the incident laser energy at a value between 32–49 mJ. The

Fig. 2. The chemical structure of (a) monomethyl ether of polyethylene oxide carboxilate (I-1) and (b) poly(ethylene glycol)methyl ether-block-poly(caprolactone)block-poly(ethylene glycol)methyl ether (PEG 4).

3.1. FTIR studies 3.1.1. PEG 1 In Fig. 3, we present typical FTIR spectra recorded in specular reflectance for PEG 1 starting material (dropcast), and PEG 1 thin films MAPLE-deposited at a fluence of 400 mJ/cm2 (a), 500 mJ/cm2 (b), and 700 mJ/cm2 (c). The absorption around 1,238 cm 1 is indicative to the C–O acid stretch. The broad absorption around 910–950 cm 1 is assigned to the –O–H deformation of the acid. The absorption around 1466 cm 1 is referring to the –CH2 groups. A broad absorption in the 2500–3300 cm 1 region is generally attributed to the –OH stretch in carboxylic acids. The broad, medium intensity features around 3425 and 3309 cm 1 together with absorptions around 1659 cm 1 are indicative of –NH2 stretching absorption in primary amines. The broad absorption around 683 cm 1 may be assigned to the – NH2 wag in aliphatic primary amine salt. Abroad absorption in the region around 2694 and 2740 cm 1 are indicative of the NH+ stretching absorption [15]. We note that MAPLE-deposited PEG 1 thin films generally retained the original PEG 1 structure even at relatively high fluences (e.g., 700 mJ/cm2), even so small changes in chain conformation and rearrangements were observed. These results confirmed that MAPLE was suited for PEG 1 transfer, generally preserving its chemical structure. 3.1.2. PEG 4 In Fig. 4, we give typical FTIR spectra recorded for PEG 4 starting material (drop cast), and PEG 4 thin films obtained by MAPLE at a fluence of 200 mJ/cm2 (a), 300 mJ/cm2 (b) and 500 mJ/cm2 (c). The main absorption bands specific to stretching vibrations C–H 2866– 2943 cm 1, carbonyl groups (1732 cm 1) and etheric function C– O–C (1097 cm 1) of copolymer are observed. The FTIR spectra of


5607

Fig. 3. Typical FTIR spectra recorded in specular reflectance for PEG 1 starting material (dropcast), and PEG 1 thin films MAPLE-deposited at a fluence of 400 mJ/cm2 (a), 500 mJ/cm2 (b), and 700 mJ/cm2 (c).

the starting material and deposited films have obvious similarities but there are noticeable shifts in several places (compare e.g., drop cast with curve a in Fig. 4). We consider therefore that further work is needed in order to optimize the processing parameter window that prevents any degradation.

3.2. AFM investigations 3.2.1. PEG 1 Fig. 5 contains the AFM micrographs of PEG 1 thin films obtained by MAPLE at a fluence of 400 mJ/cm2 (a), 500 mJ/cm2 (b),

Fig. 4. Typical FTIR spectra recorded for PEG 4 starting material (dropcast) and PEG 4 thin films MAPLE-deposited at a fluence of 200 mJ/cm2 (a), 300 mJ/cm2 (b) and 500 mJ/ cm2 (c).

5608


Fig. 5. Typical AFM micrographs of PEG 1 thin films obtained by MAPLE at a fluence of 400 mJ/cm2 (a), 500 mJ/cm2 (b), and 700 mJ/cm2 (c).

and 700 mJ/cm2 (c). We notice that the surface morphology strongly depends on incident laser fluence. At the fluence of 400 mJ/cm2 (Fig. 3a), macromolecules are aligned as statistic coils embedded in the DMSO solvent and then frozen at LN temperature. The laser beam removes the solvent by a sublimation process and a part of the statistic coils are mechanically rejected toward the substrate. Some of these statistic coils are splashed and spread on the substrate surface due to mechanical deformation. They have a disc-like shape with a diameter of 2–3 mm. At the fluence of 500 mJ/cm2 (Fig. 3b), a phase transition generates structures transformed by recrystallization. There is sufficient kinetic energy in order to spread macromolecules in bundles of macromolecule chains. Increasing the fluence a local melting/crystallization process is observed [16,17]. We observe typical structures of crystallized macromolecules organized in plate-like structures. Increasing the fluence 700 mJ/cm2, Fig. 3c, we notice an agglomeration tendency of crystallized macromolecules organized in plate-like structures, typical for a global melting/crystallization process followed by solidification.

3.2.2. PEG 4 AFM micrographs of MAPLE-deposited PEG 4 thin films at laser fluences of 200 mJ/cm2 (a), 300 mJ/cm2 (b), and 500 mJ/cm2 (c) are given in Fig. 6. As expected in this case the surface morphology also strongly depends on the laser fluence. More precisely, for relative low fluence values (about 200 mJ/cm2, Fig. 6a) a material transfer due to the superficial forces localized at the biopolymer-substrate interface is noticed. One can observe that the biopolymer macromolecular structures ‘‘align’’ on the surface following its topographic details (in case of Si the energy is minimal/micellar), while in case of Si the energy is high and a macromolecular chain alignment is produced. In case of slightly higher fluences 300 mJ/cm2, Fig. 6b the morphology is changed. The deposited thin films have a globular aspect uniformly distributed on the surface. On the other hand, the film is very thin. At higher fluences of 500 mJ/ cm2, Fig. 6c, the surface morphology has changed again and a tendency of microporous structure formation with an inhomogeneous distribution appears.


5609

Fig. 6. Typical AFM micrographs of PEG 4 thin films obtained by MAPLE at a fluence of 200 mJ/cm2 (a), 300 mJ/cm2 (b), and 500 mJ/cm2 (c).

4. Conclusions We have shown that MAPLE is appropriate to deposit a novel polyethylene glycol derivative with carboxyl functional groups and block copolymer: poly(ethylene glycol)methyl ether-block-poly(caprolactone)-block-poly(ethylene glycol)methyl ether thin films. These films had very close similarity to the starting structures obtained by drop cast. AFM investigations showed that the surface morphology depended heavily both on the laser fluence and film composition. Increasing the fluence in the case of the polyethylene glycol derivative with carboxyl functional groups MAPLE-deposited thin films the surface morphology evolved from aligned macromolecules splashed and spread on the substrate surface to typical structures of local melted/crystallized macromolecules. They further show an agglomeration tendency, typical for a global melting/crystallization process followed by solidification. We have observed by FTIR investigations that MAPLE-deposition of poly(ethylene glycol)methyl ether-block-poly(caprolactone)block-poly(ethylene glycol)methyl proceeds with no major decomposition of the starting polymeric compound. Nevertheless we consider that further work is needed in order to determine the processing parameter window that prevents significant degradation. AFM investigations have evidenced that in case of low laser

fluences the biopolymer macromolecular structures ‘‘self-align’’ on the surface following its topographic details. In case of slightly higher fluences the morphology has changed: the deposited thin film has a globular aspect uniformly distributed on the surface. At higher fluences of 500 mJ/cm2 the surface morphology has changed again and a tendency of microporous structure formation with an ununiform/inhomogeneous distribution appears. Acknowledgments R.C., C.P., A.C.P., S.G., L.D., I.N.M., I.S., A.A., O.S.I., D.M, T.B. acknowledge with thanks the financial support of this work by the Romanian Ministry for Education, Research and Youth under the Contract CEEX 60/2006 MEDINANOLAS. References [1] R. Langer, Science 293 (2001) 58. [2] D.B. Chrisey, A. Pique, R.A. McGill, J.S. Horwitz, B.R. Ringeisen, D.M. Bubb, P.K. Wu, Chem. Rev. 103 (2) (2003) 553. [3] R.A. McGill, D.B. Chrisey, Method of Producing a Film Coating by Matrix Assisted Pulsed Laser Deposition, (2000) Patent No. 6,025,036. [4] B. Toftmann, K. Rodrigo, J. Schou, P. Roman, Appl. Surf. Sci. 247 (2005) 211. [5] A. Pique´, R.A. McGill, D.B. Chrisey, D. Leonhardt, T.E. Mslna, B.J. Spargo, J.H. Callahan, R.W. Vachet, R. Chung, M.A. Bucaro, Thin Solid Films 355–356 (1999) 536.

5610


[6] P.K. Wu, J. Fitz-Gerald, A. Pique´, D.B. Chrisey, R.A. McGill, MRS Proceedings 617 (2000), J2.3 1-6. [7] C.E. Allmond, A.T. Sellinger, K. Gogick, J.M. Fitz-Gerald, Appl. Phys. A: Mat. Sci. Process. 86 (4) (2007) 477. [8] R. Cristescu, G. Dorcioman, C. Ristoscu, E. Axente, S. Grigorescu, A. Moldovan, I.N. Mihailescu, T. Kocourek, M. Jelinek, M. Albulescu, T. Buruiana, D. Mihaiescu, I. Stamatin, D.B. Chrisey, Appl. Surf. Sci. 252 (2006) 4647. [9] R. Cristescu, M. Jelinek, T. Kocourek, E. Axente, S. Grigorescu, A. Moldovan, D.E. Mihaiescu, M. Albulescu, T. Buruiana, J. Dybal, I. Stamatin, I.N. Mihailescu, D.B. Chrisey, J. Phys.: Conference Series 59 (2007) 144. [10] M. Jelinek, R. Cristescu, E. Axente, T. Kocourek, J. Dybal, J. Remsa, J. Plestil, D. Mihaiescu, M. Albulescu, T. Buruiana, I. Stamatin, I.N. Mihailescu, D.B. Chrisey, Appl. Surf. Sci. 253 (19) (2007) 7755.

[11] A. Doraiswamy, R.J. Narayan, R. Cristescu, I.N. Mihailescu, D.B. Chrisey, Mat. Sci. Eng. C 27 (2007) 409. [12] R. Cristescu, T. Kocourek, A. Moldovan, L. Stamatin, D. Mihaiescu, M. Jelinek, I. Stamatin, I.N. Mihailescu, D.B. Chrisey, Appl. Surf. Sci. 252 (2006) 4652. [13] R. Cristescu, T. Patz, R.J. Narayan, N. Menegazzo, B. Mizaikoff, D.E. Mihaiescu, P.B. Messersmith, I. Stamatin, I.N. Mihailescu, D.B. Chrisey, Appl. Surf. Sci. 247 (2005) 217. [14] R. Cristescu, D. Mihaiescu, G. Socol, I. Stamatin, I.N. Mihailescu, D.B. Chrisey, Appl. Phys., A 79 (2004) 1023. [15] KnowItAll Database by Bio-http://www.bio-rad.com. [16] S.N. Magonov, M.-H. Whangbo, Surface Analysis with STM and AFM, VCH, Weinheim, 1996, p. 323. [17] M.-H. Whangbo, S.N. Magonov, H. Bengel, Probe Microscopy 1 (1997) 23.