Mat. Res. Soc. Symp. Proc. Vol Materials Research Society. Novel Growth of Biodegradable Thin Films via Matrix Assisted Laser Processing

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1 Mat. Res. Soc. Symp. Proc. Vol Materials Research Society Y4.4.1 Novel Growth of Biodegradable Thin Films via Matrix Assisted Laser Processing A.L. Mercado 1, J.M. Fitz-Gerald 1, R. Johnson 2, and J.D. Talton 3 1 University of Virginia, Dept of Materials Science and Engineering 2 University of Virginia, Dept of Chemistry Charlottesville, VA Nanotherapeutics Inc, Alachua, FL ABSTRACT The ability to controllably deposit polymers onto flat or curved surfaces in a quasi-dry environment while retaining native-like structure is of extreme importance to the medical and microelectronics communities. Current applications range from protective and conformal coatings for microelectronics to sustained drug delivery platforms in the pharmaceutical industry. In this research, biodegradable thin films of poly(dl-lactide-co-glycolide) (PLGA), were deposited onto flat substrates of Si and NaCl using a pulsed excimer laser, (λ=248nm)with fluences ranging from J/cm 2 via matrix assisted pulsed laser evaporation (MAPLE). Results are shown from scanning electron microscopy (SEM) to study morphological features and Fourier Transform Infrared Spectroscopy (FTIR), and Nuclear Magnetic Resonance (NMR) to measure chemical structure compared to original PLGA. INTRODUCTION Next generation applications require tighter tolerances on the structural, morphological, and chemical composition of thin film surfaces. This is especially the case for the deposition of high quality thin films of organic or thermoplastic or low Tg polymeric materials as opposed to purely inorganic materials where high temperatures and native oxides are used to overcome the hurdles in their fabrication. Depending on the particular application, it may be desirable to deposit films containing single or multilayer structures of different organic or polymeric materials, homogeneous composite materials, or materials with graded compositions. 1,2 In many situations, it will be necessary to deposit discrete films, achieve conformal coverage, and provide high quality structures, especially in regard to surface coverage uniformity and thickness control. Thin films of polymeric, inorganic and organic materials also play an important role in batteries, high performance dielectrics, optical data storage, optical communications and displays based on organic electroluminescent materials. 3,4,5,6 Polymer and organic coatings are also essential for the fabrication of chemical and biochemical sensors 7,8, and in biomedical applications ranging from passivation films for prosthetic or implanted devices to microencapsulation of drugs for targeted delivery systems. 9,10,11 EXPERIMENTAL DETAILS Matrix assisted pulsed laser evaporation was developed by the Naval Research Laboratory in order to controllably deposit complex organic thin film coating for use with chemical sensors. 12 Complete details of this technique and related experiments have been reported. 13

14,15 Solvents that are sufficiently volatile and do not form a film once evaporated by the laser are ideal.

2 Y4.4.2 In MAPLE processing, the target consists of a polymer dissolved in a UV absorbing solvent with high vapor pressure. The purpose of the volatile solvent in the target is to aid desorption a majority of the laser energy and vaporize when the laser energy is converted to thermal energy by photochemical processes. 14,15 Solvents that are sufficiently volatile and do not form a film once evaporated by the laser are ideal. Due to the solvent s high vapor pressure the molecules of the solvent leave the target with high kinetic energy and collide with the polymer. These collisions transfer the polymer molecules to the substrate via entrainment processes. All films were deposited at room temperature using a pulsed excimer laser (λ=248 nm) operating at 5 Hz with a 25 ns pulse (FWHM) in an experimental configuration as shown in Figure 1. In this study, 1 wt% PLGA 75/25 (75% LA, 25% GA, Birmingham Polymers), (basic structure is shown in Figure 1 inset), was dissolved in chloroform (CHCl 3 ) and vortex mixed for 20 minutes to dissolve the polymer uniformly. Chloroform was chosen as a solvent in this study due to a relatively high absorption at 248 nm (43% cm -1 ) and lower freezing point (-63 C). The solution was poured into a Cu container and flash frozen in liquid nitrogen (LN 2 ). The solid composite polymer/chcl 3 target was then inserted onto a LN 2 cold stage (temperature ~100 K). After insertion of the target, the system was pumped down to a base pressure of 10-6 Torr, and then backfilled to 100 mtorr with Ar. Experiments were conducted between 0.1 J/cm 2 to 1.0 J/cm 2, while operating at a repetition rate of 5 Hz. PLGA molecule H C H (a) O C O (b) cold stage laser pulse frozen target laser pulse (c) substrate RESULTS AND DISCUSSION volatile solvent is pumped away Figure 0. Schematic illustrations of the basic structure of PLGA (a) and of the matrix-assisted laser processing setup for thin film deposition of PLGA onto flat and curved (particulate) substrates (b,c). In order to properly evaluate whether the chemical integrity was changed after ablation, Fourier transform infrared spectroscopy (FTIR) of films and nuclear magnetic resonance (NMR) of dissolved films were performed. Figure 2 shows both native PLGA (a) and MAPLE deposited PLGA FTIR spectra (b). The results from the FTIR spectra show that the deposited films resemble the native polymer to a finite degree. Overall, characteristic peaks at 1700 cm -1 and fingerprint regions at 1450 cm -1 appeared similar, however, there was an additonal peak at 760 cm -1 not visible in the native PLGA profile that could be identified as C-Cl stretch (Figure 2b.). 16 The FTIR results are not conclusive evidence in part due to the film thickness. 17 Therefore nuclear magnetic resonance (NMR) was used for further analyze potential decomposition. NMR spectra of the native PLGA and high-energy MAPLE samples are shown in Figure 3 (a). Double peaks at 1.6 ppm represent hydrogens in the lactic acid CH 3 side groups,

3 Y4.4.3 while the multiplets at 4.8 ppm and 5.2 ppm represent the intrachain glycolic acid CH 2 groups and the lactic acid CH units, respectively. The complex nature of the peaks at 4.8 and 5.2 ppm arise from the varying lactic acid and glycolic acid sequences in the polymer backbone. 18 The NMR spectra in Figure 3 (b), (c) show credible evidence that a portion of the polymer was degraded to a lower MW species (a) C-H Stretch (b) OH %Transmission C-H stretch C-H bend Normalized 0.1 J/cm PL G A 75/25 N ative 0.15 J/cm J/cm J/cm -2 C-H Bend C=O W avenum bers (cm -1 ) J/cm J/cm J/cm C=O W avenum bers (cm -1 ) Figure 2. FTIR spectra for native (a) and MAPLE deposited PLGA (b). The strong correlations of the fingerprint regions at 1200 cm -1 and the C-H stretch between the native and deposited films gives an indication that the backbone of the deposited PLGA is largely intact following deposition.? N a t i v e (a) 1. 0 J /c m P P M J/cm 2 4,000 pulses 100 mtorr Ar Deuterated Chloroform CDCl 3 (b) N a t iv e 0.2J 0.56J 0.76J (c) 0.76 J/cm 2 0.4J 1.0J 0.56 J/cm J/cm J/cm 2 Native PPM P P M Figure 3. Nuclear magnetic resonance spectra from native and deposited materials to evaluate the decomposition effects due to laser-solid interactions. Figure 3(a) shows a comparison of the native material to the MAPLE deposited material at 1.0 J/cm 2. Figures 3(b,c) show the comparison of the native to MAPLE deposited films at fluences ranging from J/cm 2.

4 Y4.4.4 With increasing laser fluence the NMR spectra broadens at 1.6, 4.8, and 5.2 ppm, respectively, indicating either a higher signal: noise ratio due to a lower percentage of polymer in solution or an increase in decomposition products. At higher energies, a trend in decomposition of the deposited PLGA to lower molecular weight species, which are chemically identical, may be observed with differing mobilities, stemming from the breaking of lactic acid and glycolic acid chains. 18 These effects are more pronounced in Figure 3(c) where the spectra are combined. Scanning electron microscopy (SEM) was performed to gain insights into the thickness and morphological characteristics of the deposited materials. SEM micrographs in figure 4 show differences in the surface morphology and film thickness on laser fluence. All of the films deposited, regardless of laser energy, had varied amounts of surface features and 'matrix trace patterns' on the surface. At higher fluences, the particulate population (25nm - 500nm) becomes more pronounced and apparent matrix effects are minimized as shown in Figure 4(a-g). Typical thin film thickness was measured to be on the order of nm in Figure 4(h-i). (a) 0.10 J/cm 2 (b) 0.15 J/cm 2 (c) 0.20 J/cm 2 (d) 0.40 J/cm 2 1µm 1µm 1µm (e) 0.56 J/cm 2 (f) 0.76 J/cm 2 1µm 1µm 1µm (g) 1.0 J/cm 2 (h) 0.40 J/cm 2 (i) 1.0 J/cm 2 1µm 100 nm 100 nm Figure 4. Scanning electron microscope images of deposited thin films of PLGA. The SEM micrographs show trends of particulate formation, showing morphology effects in terms of matrix patterns, particle roughness and droplet formation as a function of laser fluence (a-g). Figure 4 (g, h) illustrate the thickness regime for the films which ranged from nm, (images were taken at 50, 15 tilt, respectively). A comparison with conventional UV-PLD (no solvent) has been performed on solid targets of PLGA in similar energy regimes from (0.2-1 J/cm 2 ). These results demonstrate similar chemical structures to MAPLE deposited PLGA. 19 The chemical degradation from the NMR spectra (broadening) overlap with the MAPLE deposited data, while the roughness of the films at lower

5 Y4.4.5 energies is reduced by an order of magnitude. The deposition rate at higher fluence increases by an order of magnitude, suggesting the clear increase over MAPLE without compromising surface morphology. Figure 5 shows a comparison to the MAPLE work at both ends of the energy spectrum ( J/cm 2 ) indicating the morphology and chemical structure of thin films of PLGA deposited by conventional UV PLD. (a) (b) (c) (d) 10 µm 100 nm 1 µm 10 µm N a t iv e J / c m -2 (e) J / c m J / c m P P M Figure 5. Initial results PLGA films made by conventional UV PLD. Figures (a),(b) represent smooth films deposited at 0.2 J/cm 2, a scratch was made due to lack of morphology and thickness measurement. Figures (c),(d) represent films deposited at the highest fluence, 1.0 J/cm 2, showing significant roughness and increases in deposition rates. The NMR spectra (e) suggest that the amount of degradation at low fluence is similar to that found in the MAPLE deposited materials at 248nm CONCLUSIONS AND FUTURE WORK In conclusion, we have demonstrated successfully the ability to deposit thin films of a fragile biodegradable polymer using matrix assisted laser processing (MAPLE) with native-like signatures as obtained from FTIR and NMR characterization. The ability to control the deposition rate for thin films ranging from 20nm-100nm is an important aspect of the MAPLE process. The surface roughness of the deposited films was significantly higher than expected and further matrix / polymer optimization is required. Significant broadening of the NMR spectra indicate the breakdown of the polymer into lower MW species, which suggests that due to PLGA s high absorption at 248nm, MAPLE deposited films will not retain 100% chemical integrity.

6 Y4.4.6 ACKNOWLEDGEMENTS The authors would like to acknowledge Raj Bansal and Dr. Cassandra Fraser for their contributions to microscopy and characterization. REFERENCES R. Dagani, Ch. Eng. News 77, 25, Accounts of Chemical Research, 32, Issue 5 (1999). R.A. McGill, A. Piqué, D.B. Chrisey, J.M. Fitz-Gerald, V. Nguyen, R. Chung, Laser Processing of Polymers and Conductive Materials for the Fabrication of Conductive Composite Coatings: Applications with Chemical Sensors, Proc. Sixth International Conference on Composites Engineering, ICCE/6 Orlando, FL, 563 (1999). A.C. Edrington, A.M. Urbas, P. DeRege, C. Chen, T. Swager, M. Hadjichristidis, M. Xeridou, L.J. Fetters, J.D. Joannopoulos, Y. Fink, E.L. Thomas, "Polymer Based Photonic Crystals" Adv. Mater., 13, 421, (2001). Y. Okamoto, "Lanthanide Metal Polymer Complexes, Synthesis, Characterization and Application" Makromol. Chem., Macromol. Symp., 59, 82, (1992). C. Du, L. Ma, Y. Xu, W. Li, "Synthesis and Fluorescent Properties of Europium-Polymer Complexes Containing Napthoate and 1,10-Phenanthroline Ligands" J. Appl. Poly. Sci., 66, 1405, (1997). A.L. Jenkins, G.M. Murray, "Polymer-Based Lanthanide Luminescent Sensors For Detection of the Hydrolysis Product of the Nerve Agent Soman in Water" Anal. Chem., 71, 373, (1999). R.A. McGill, M. H. Abraham, et al., Choosing Polymer Coatings for Chemical Sensors, Chemtech 24(9): 27-37, (1994). B.R. Ringeisen, J. Callahan, P. Wu, A. Pique, B. Spargo, R.A. McGill, M. Bucaro, H. Kim, D.M. Bubb, and D.B. Chrisey, Novel Laser-Based Deposition of Active Protein Thin Films,Langmuir 17, (2001). A. Hickey, Efficacy of rifampicin-poly(lactide-co-glycolide) microspheres in treating tuberculosis, in Respiratory Drug Delivery VI., Hilton Head, SC: Interpharm Press, Inc., (1998). D.A. Edwards, Large porous particles for pulmonary drug delivery. Science, 276 (5320): p , (1997). A. Gopferich, M.J. Alonso, R. Langer, Development and characterization of microencapsulated microspheres, Pharm Res, 11(11): p , (1994). R.A. McGill and D.B. Chrisey, MAPLE patent, Navy case No.78,117, (1999). D. B. Chrisey, R. A. McGill, J.S. Horwitz, A. Pique, B. R. Ringeisen, D. M. Bubb, and P. K. Wu, Laser Deposition of Polymer and Biomaterial Thin Films, Chem. Rev., 103, (2003) L. Zhigilei, E. Leveugle, B.J. Garrison, Y.G. Yingling, and M. Zeifman, Computer Simulations of Laser Ablation of Molecular Substrates, Chem. Rev, 103, , (2003). K. Dreisewerd, The Desorption Process in MALDI, Chem. Rev, 103, (2003). D. M. Bubb, P. K. W., J. S. Horwitz, J. H. Callahan, M. Galicia, A. Vertes, R. A. McGill, E. J. Houser, B. R. Ringeisen, and D. B. Chrisey The effect of the matrix on film properties in matrix-assisted pulsed laser evaporation. Journal of Applied Physics A 91(4): (2002). D.A. Skoog, Principles of Instrumental Analysis, Chapter 11, Saunders (1997). J.S. Hrkach, R. Langer, Nanotechnology for biomaterials engineering: structural characterization of amphiphilic polymeric nanoparticles by 1 H NMR spectroscopy. Biomaterials 18(1): 27-30, (26 April 1996). J.M. Fitz-Gerald, A. L. Mercado, Pulse Laser Deposition of Biodegradable Thin Films: A Comparison of Matrix Assisted and Conventional Methods, J. of Materials Research (manuscript in prep) April 2003.

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