Analytica Chimica Acta 808 (2014) 10–17

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Review

Mass spectrometric imaging of synthetic polymers Anna C. Crecelius a,b,∗ , Jürgen Vitz a,b , Ulrich S. Schubert a,b,c a

Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany c Dutch Polymer Institute (DPI), John F. Kennedylaan 2, 5612 AB Eindhoven, The Netherlands b

h i g h l i g h t s

g r a p h i c a l

a b s t r a c t

• Principals of mass spectrometric imaging (MSI) of synthetic polymers.

• The ionization techniques SIMS and MALDI for MSI are compared.

• A short perspective about polymer blend SIMS-MSI is presented.

• An overview of recent applications and future prospects is given.

a r t i c l e

i n f o

Article history: Received 27 April 2013 Received in revised form 1 July 2013 Accepted 9 July 2013 Available online 16 July 2013 Keywords: Mass spectrometric imaging Polymers MALDI SIMS

a b s t r a c t The analysis of synthetic polymers represents today an important part of polymer science to determine their physical properties and to optimize the performance of polymeric materials for block copolymers as well as blend systems. The characterization can easily and rapidly be performed by mass spectrometry. In particular, the film formation of a synthetic polymer is of interest in material research and quality control, which can be determined by employing mass spectrometric imaging (MSI) using secondary ion mass spectrometry (SIMS) or matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. MALDI-MSI has been rapidly improved for the analysis of tissue cross-sections due to its soft ionization and accessible m/z range, which both also play an important role in polymer science. On the other hand, SIMS-MSI enables a sub-micrometer molecular spatial resolution, which is limited in MALDI-MSI due to the spatial resolution capabilities of the laser desorption process. The aim of the present contribution is to summarize recent advances in both imaging techniques for the analysis of synthetic polymers and to highlight their capabilities to correlate several imaging modalities in future applications. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Principals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recent applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany. Tel.: +49 3641 9482 38; fax: +49 3641 9482 02. E-mail address: [email protected] (A.C. Crecelius). 0003-2670/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.aca.2013.07.033

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Anna C. Crecelius graduated with a Dipl. Ing. (FH) at the Hochschule Fresenius in 1999 and obtained her Ph.D. at the Sheffield Hallam University in U.K. in 2002. She has conducted post-doctoral research stays at universities including Vanderbilt University (Nashville, TN, USA) and Ludwig Maximillian Universität München. Currently, she is a research fellow at the Friedrich Schiller Universität Jena in the research group of Prof. Ulrich S. Schubert, leading the mass spectrometry activities. Her publication record shows over 35 refereed articles including one book chapter, with an H-index of 14 and over 633 citations.

Jürgen Vitz received his diploma degree in 1999 and obtained his Ph.D. in 2004 under the supervision of Prof. Karsten Krohn at the University of Paderborn. In 2006 he moved to the group of Stéphanie Legoupy at the Université du Maine (Le Mans, France) as a post-doctoral fellow. Thereafter, in 2007, he joined the group of Prof. Ulrich S. Schubert at the Eindhoven University of Technology (TU/e; Netherlands) and, in 2009, he changed to the Friedrich Schiller University Jena (Germany). His research is focused on polymerizations using high-throughput approaches, including organic synthesis, catalysis as well as ionic liquids as alternative reaction media.

1. Introduction Soft ionization mass spectrometry is a powerful characterization technique in polymer science to gain information about the molar masses, polydispersity index values, and end-group structures of synthetic polymers [1,2]. These physical properties are in particular important for tailor-made polymers in high-performance application fields, e.g., health care, life science, car or aviation industries. Besides, the macroscopic as well as microscopic surfacecomposition of these polymers is of high interest, which can easily be figured out by employing mass spectrometric imaging (MSI). This imaging technique of soft surfaces, including organic, polymeric, and biological material, has been remarkably advanced lately, as indicated by the enormous increase in the number of publications as presented in Fig. 1a. However, MSI analysis of synthetic polymers plays only a very minor role even though the number of publications has been raised recently (see Fig. 1b). Most publications are still concentrated on biomedical tissue applications (for an in depth study of relevant developments in this area the reader is referred to Ref. [3]). The aim of this contribution is to highlight the potentials of MSI in the field of synthetic polymers by explaining its principals, providing an overview of recent applications and future prospects to inspire more researchers to use this emerging technique. Visualizing methods will be one of the exploding characterization tools in analytical chemistry and its combination to gain substantial information will be one of the main approaches. 2. Principals Mass spectrometric imaging utilizes a probe (primary ions or a laser) to sputter or desorb species directly from the surface, as illustrated in Fig. 2 (step 1). The generated ions are subsequently separated in a corresponding analyzer and detected. A typical analyzer used in MSI for analyzing synthetic polymers by MALDI and SIMS is a time-of-flight (TOF) analyzer in which the time is recorded that the ions require

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Ulrich S. Schubert studied chemistry in Frankfurt and Bayreuth and the Virginia Commonwealth University, Richmond (USA). His Ph.D. studies were performed at the Universities of Bayreuth and South Florida/Tampa (USA). After postdoctoral training with Jean-Marie Lehn at the University in Strasbourg (France), he moved to the TU München and obtained his Habilitation in 1999. From 1999 to 2000 he was Professor at the Center for NanoScience, University of Munich, and from 2000 to 2007 Full-Professor at TU Eindhoven (The Netherlands). Currently he holds a chair at the Friedrich Schiller University Jena with research interest in nanoparticle systems as sensor and drug delivery devices, supramolecular chemistry, inkjet printing of polymers, polymers for energy applications, and self-healing materials.

reaching the detector. To obtain an image of the polymer material, not only one position is analyzed, rather a x,y – pattern is analyzed from which always a mass spectrum is generated as presented in Fig. 2 (step 2). This is typically achieved by a movable stage. The final step in a MSI analysis (see Fig. 2, step 3) is to generate ion images from different mass signals by using certain software packages, which can either be purchased with the mass spectrometer or can be downloaded from a non-commercial source [4]. Mainly the two ionization techniques, namely SIMS [5] and MALDI [6,7] are currently used to investigate synthetic polymer surfaces. The reader is recommended to Ref. [8] by Mahoney for an in-depth coverage of SIMS in the field of polymer science. Both techniques, SIMS and MALDI, are very complementary as outlined in Table 1. The main advantage of MALDI-MSI is the theoretically unlimited m/z range due to the TOF analyzer and its soft ionization, yielding intact species. However, MALDI-MSI can certainly not compete with the spatial resolution of SIMS-MSI, which can be 100 nm as reported in Ref. [9]. Instead, the highest resolution of MALDI-MSI is up to now in the range of 1–5 ␮m [10,11]. A more detailed comparison of the benefits and challenges of both imaging techniques is provided in Table 2. SIMS owns an excellent surface sensitivity, which requires a clean performed sample preparation to avoid any contamination. To achieve higher sensitivities and an increase in the m/z range for SIMS-MSI the surface can be covered with a typical organic MALDI matrix, such as 2,5-dihydroxybenzoic acid (DHB) [12]. In the case of matrix-enhanced ME-SIMS, DHB can be electrosprayed to obtain fine crystals, which enables a spatial resolution of below 3 ␮m and a reachable m/z range up to 2500 for the imaging experiments. Another possibility to enhance the sensitivity is to evaporate a metal, such as gold, on the polymer surface. With this sample pretreatment, the SIMS-MSI analysis of a poly(styrene) coating with a molar mass above 1000 was possible [13] without the necessity to lower the spatial resolution. Finally, the combination of both approaches, the coating of the surface with an organic MALDI matrix and afterwards with a metal layer, was also tested, enhancing the achievable m/z range without decreasing the spatial resolution [14]. A sub-monolayer coverage of metal nanoparticles strengthened as well the SIMS signals of the analyzed polymer films [15]. The sample preparation required for MALDI-MSI is very crucial for imaging polymer surfaces, as the homogeneity of the matrix–polymer mixture greatly influences the quality of the recorded MSI data [16,17]. Even the temperature plays an important role, as presented in Fig. 3 for the dried-droplet preparation of PEG 1000. At elevated temperatures the polymer is higher concentrated at the outer rims of the shown droplets (A, B, and C).

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Fig. 1. Number of publications each year by performing a literature search on Web of Knowledge using the key words (A) “mass spectrometry imaging” and (B) “mass spectrometry imaging synthetic polymers” (date of search: 25.06.2013).

Fig. 2. Principals of MSI.

The selection of the optimum matrix for analyzing the desired polymer is highly important, too. For example, if dithranol is used to analyze 2,2,6,6-tretramethylpiperidine-N-oxyl (TEMPO)-capped poly(styrene), only fragments are visible without the TEMPO endgroup. This can be easily avoided by using DHB instead [18]. Therefore, the Polymers Division of the National Institute of Standards and Technology (NIST) has developed a database, published on a webpage, where the best matrix for a series of polymers is listed [19]. New ideas in this field are to use metals, e.g., cobalt powder, to analyze poly(ethylene) [20], to sputter silver layers on biological tissue for the determination of olefins by MSI [21] or to use porous silicon as substrate [22]. A variety of approaches have been tested in our group [23] to apply the organic MALDI matrix homogeneously on top of the polymer films without changing the lateral film distribution, such as the Table 1 Comparison of characteristics in MALDI- and SIMS-MSI. Feature

MALDI-MSI

SIMS-MSI

Probe m/z range 3D-imaging Spatial resolution

Laser Above 100,000 Multiple sections 1–150 ␮m

Primary ions Below 2000 C60 + sputtering 100 nm

use of a TLC reagent sprayer or the ImagePrepTM (Bruker Daltonics). However, the best results were achieved by spin-coating a mixture of organic matrix, salt and polymer on top of the substrate (ITOcoated glass slide). Nonetheless, Weidner and Falkenhagen [24] figured out that electrospraying of both, matrix and polymer, yields the best results for analyzing the compositions of a poly(ethylene oxide)/poly(propylene) copolymer after chromatographic separation.

3. Recent applications The number of publications in the field of MSI of polymer surfaces is small, compared to the popularity in life science as discussed in the introduction. However, the quality of studies in this field has improved in recent years due to a superior performance current mass spectrometers. Even though, the number of publications employing MALDI-MSI to analyze polymer surfaces is still half of the one for SIMS-MSI. Possible reasons can be the later development, the lower resolution capabilities as well as the additional use of an organic matrix. The first study on MALDI-MSI of synthetic polymers was performed by Klerk in his PhD thesis [25]. He reported the simultaneous analysis of poly(ethylene glycol) and rhodamine 6G by

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Table 2 Pro and cons of MALDI- and SIMS-MSI. Technique

Pros

Cons

MALDI-MSI

• Widest mass range available • High sample tolerance

• Sample must be covered by an organic matrix • Interfering peaks below m/z 300, if organic MALDI matrix is used

SIMS-MSI

• Highest spatial resolution achievable, however less material is ejected causing a sensitivity decrease and extensive fragmentation due to the higher energy deposition • Wide variety of primary ion guns available

• Source-induced fragmentation

Fig. 3. MALDI-MSI ion images of (A) [PEG]19 K+ , (B) [PEG]23 K+ , and (C) [PEG]29 K+ with DHB in water at different temperatures. Kind courtesy from S.J. Gariel and S. Weidner, presented at the Belgian-German Molecular Meeting in Luxemburg, December 2012.

spotting both compounds on different positions on the target and spray-coating the matrix. The analysis of synthetic polymers and biomolecules was described as challenging owing to the specific sample preparation required for these two substance classes. The feasibility to use MALDI-MSI for generating polymer ion images was recently reported by us as well [23]. We could show that crosslinking is occurring in poly(styrene) (PS) films, when irradiated

• Small sampling area

with UV light, which caused a signal reduction of the polymer, as presented in Fig. 4. Different UV irradiation times were investigated to distinguish between non-irradiated and irradiated surfaces for which an aluminum mask with holes was used as shown in the left corner in Fig. 4. Due to a possible heat transfer through the mask, a depression of the polymer signals under the mask could even be detected beyond a 24 h UV irradiation time. A recent review by Mahoney and Weidner focuses on the surface and imaging techniques of polymers and is highly recommended for additional information [26]. For industrial and commercial applications, often blends are used to improve and to adjust the properties needed [27]. In addition, blending of materials is a cheap and efficient method to produce new polymer systems avoiding costly and long approval procedures. Most binary polymer pairs are immiscible and produce bulk phase separated materials on blending [28]. However, the surface composition can vary from the bulk. Therefore, often SIMS-MSI was used in the past to generate chemical images from the blend system at the surface due to its good spatial resolution, selectivity and sensitivity. A variety of blend systems, studied by this imaging technique, are summarized in Table 3. From the numerous examples one is selected to demonstrate the capability of SIMS-MSI to evidence phase separation phenomena [39]. By varying the ratio of PS and P2VP in a blend to functionalize insulating surfaces, different structures can be obtained. By a high relative content of PS, entangled wires are obtained as shown in the ion images in Fig. 5 of the fragments PS, or P2VP, respectively. The bright yellow color represents high, the dark color low intensity signals. By comparing Fig. 5(A) and (B), the correspondence between both polymer distributions is obvious.

Fig. 4. MALDI-MSI ion images of [PS]40 Ag+ , [PS]41 Ag+ and [PS]44 Ag+ ions at different UV irradiation time points (15, 120, 240 min, 24, 48, 72 h) (pixel size 150 ␮m). Top left: optical image of the PS film covered by the aluminum mask (corresponds to the area analyzed by MALDI-MSI). Reproduced from [23] with permission from John Wiley & Sons, Ltd.

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Table 3 Reference list for blend systems characterized by SIMS-MSI. Blend system

Reference

Poly(vinyl chloride)/poly(methyl methacrylate) Poly(methyl methacrylate–b-(2-perfluoro hexyl ethyl)acrylate)/poly(methyl methacrylate) ethylene-tetra fluoroethylene/poly(methyl methacrylate) Poly(styrene)/poly(methyl methacrylate) Poly(ε-caprolactone)/poly(vinyl chloride) Poly(l-lactic acid)/pluronic/protein Poly(ethylene)/poly(propylene) Poly(styrene)/poly(butadiene) Poly(styrene)/poly(2-vinylpyridine)

The SIMS-MSI experiments can additionally be expanded to the characterization of films generated by only one polymer component obtaining certain self-organized formations, such as, e.g., a honeycomb microstructure in PS [40], flat lamella in poly(bisphenol-A-ether alkane) [41], and hexaogonally arranged pores in poly(styrene)-b-oligo(thiophene) block copolymers [42]. SIMS-MSI is a well suitable analytical technique for the inspection of photolitographic processes, too, as presented by the Castner group [43]. One of the challenges in photolitography is that

PVC/PMMA PMMA-b-PFHEA/PMMA ETFE/PMMA PS/PMMA PCL/PVC PLLA/pluronic/protein PE/PP PS/PB PS/P2VP

[29–31] [32] [33] [34] [35] [36] [37] [38] [39]

photoresist residues remain present after the processing step. The other critical point in photolitography is the quality of the illumination step, which can be checked by MALDI-MSI as shown recently [44]. For this purpose, a negative photoresist layer was prepared by spin-coating the main component novolac, benzophenone as the active component, the organic MALDI matrix dithranol and the salt additive LiTFA. A transparency with a printed wiring diagram, as shown in Fig. 6 (black/white image), was placed on the negative photolayer and irradiated for 15 min. The following MALDI-MSI analysis of the main component novolac revealed the red ion images, as presented in Fig. 6. For the generation of the ion images, all related signals of the novolac resin (different oligomer signals) were summed up. This example in the area of printed circuit boards (PCB) shows remarkably the value of MALDI-MSI, since the success of the illumination step can be easily checked and in case of an unsuccesful illumination step, the substrate can be used again by applying a new photoresist and a defined mask, in particular if expensive PCB material is used. Polymers do not only play an important role in one or more component systems, such as films, blends, or photoresists as described above, but also in special coatings. Herein, coating defects are of major interest, in particular in the car industry. One suitable analytical technique to examine the chemical composition, and thus defects, is SIMS [45]. But of course, other imaging methods can be applied, too. As recently shown, commercial pigments can be easily identified by laser desorption/ionization (LDI) [46] and this work motivated us to investigate commercial car coatings by LDIMSI using the signal for the blue pigment, as illustrated in Fig. 7. The scratch in the middle of the base coat is clearly visible in the recorded ion image. We currently extend the study of car coatings by the analysis of the different layers (primer, base coat, and clear coat). LDI-MSI has the advantage over MALDI-MSI that no organic matrix is required reducing the sample preparation step and allowing a higher lateral resolution. Typically, secondary metabolites in

Fig. 5. SIMS-MSI ion images (sum of intensities) of (A) PS and (B) P2VP in a PS/P2VP blend in a ratio 15:1.

Fig. 6. Overlay of MALDI-MSI ion images (sum of intensities) of the negative photoresist layer (red images) over the printed wiring diagram. (For interpretation of the references to color in this figure caption, the reader is referred to the web version of the article.)

Adapted from [39] with permission from Elsevier.

Adapted from [44] with permission from the American Chemical Society.

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Fig. 7. LDI-MSI analysis of the blue pigment in a commercial automotive coating. The negative spectrum shows the signal of the pigment at m/z 575. A scratch in the automotive coating, shown in the optical image on the left inset, is readily detectable by LDI-MSI, as presented in the ion image of the signal in the right inset (pixel size: 50 ␮m).

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Fig. 8. MALDI-MSI analysis of luminal membrane surfaces at a laser raster of 100 ␮m. (A) Typical mass spectrum, (B) and (C) ion images of PSO and PVP, respectively, and (D) overlay. Adapted from [66] with permission from the American Chemical Society.

various plants are analyzed by this imaging approach at a spatial resolution of 10 ␮m [47]. The usefulness of SIMS-MSI to determine the surface composition of hydrogels was demonstrated by two approaches: the presence of collagen in poloxamine hydrogels [48] and the functional group N-hydroxysuccinimide reactive ester in PEG-based hydrogels [49]. Another emerging area where polymers play an important role are organic light-emitting diodes (OLEDs), which nowadays are already used in passive-matrix as well as active-matrix flat panel displays but also for special lighting applications, for example. OLEDs, consisting of polymers instead of a semiconductor material, have the advantage that they can be directly printed on different substrates, e.g., using an inkjet printer [50,51], and allowing a wide range of applications, e.g., for extremely thin and flexible displays (shown at CES 2013 in Las Vegas). Polymer chains in OLEDs can either fold themselves creating stiff straight segments, or unfold creating randomly oriented segments depending on the fabrication process. Furthermore, a phase separation can occur when mixing blends with small molecules bearing a different structure which affects the performance of the electronic device. Thus, the characterization of the nanostructures of OLEDs is crucial for their efficiency. In order to clarify their nanostructures, SIMS-MSI can be used as presented in Refs. [52–54]. The discovery of new polymer material can efficiently be performed by a high-throughput combinatorial approach, in which SIMS-MSI is used as the characterization tool yielding high quality spectra [55,56]. In this high-throughput approach often inkjet printing [57] is employed to create micro-arrays [58] as shown for acrylate monomers [59] and drug/polymer formulations [60]. The use of polymers in the medical field, for example as drugdelivery systems, is gaining more and more interest [61,62]. In particular for the pharmaceutical industry, the correlation between processing, structure, and drug release are of special importance. One image modality, which can be applied to gain further information about this, is certainly SIMS-MSI as recently convincingly reported [63,64]. Polymer-drug systems play a very important role in cardiac stents, too, to treat restenosis or re-narrowing arterial walls, where SIMS-MSI is very useful for depth profiling. The introduction of a drug within a biocompatible polymer matrix that is coated onto the exposed surface of a stent can eliminate tissue

growth. In a recent study, the surface of a styrene-b-isobutyleneb-styrene triblock copolymer containing the drug paclitaxel was investigated by a SIMS instrument equipped with a 15 keV Ga+ and 20 keV C60 + ion source [65]. The C60 + ion source enabled a higher detection on the surface without any alterations. A quite recent medical application of polymers deals with dialyzer membranes, consisting of poly(sulfone) (PSO) and poly(vinyl pyrrolidone) (PVP), which were investigated by MALDI-MSI regarding their chemical structure and localization [66]. Not only flat membranes, but also hollow fiber membranes were analyzed. The polymers were homogeneously distributed in both membrane types, as shown in Fig. 8. In the area of drug-delivery systems, the combination of several image modalities is highly important since it is necessary to combine the chemical information to gain a complete picture. One selected study is the combination of SIMS-MSI and Raman microscopy of rapamycin coatings in poly(lactic-co-glycolic acid) (PLGA) [67]. The next prospective step is the correlation between different image modalities to compare the complementary information pixel-by-pixel. However, this is a challenging task as described in a recent review [68]. Nonetheless, instruments have been developed already which allow the simultaneous SIMS-MSI and confocal Raman microscopy analysis from the same surface area. In the medical field, three-dimensional imaging plays a substantial role and the demand on molecular characterization techniques in 3D is increasing. A review about three-dimensional SIMS-MSI studies covers the time period up to 2007 [69]. Therefore, three newer examples have been selected for a closer look. Two subsequently studies deal with polymeric based drug-elution stent coatings, in which sirolimus was used as drug candidate and PLGA as polymer matrix [70,71]. 3D-SIMS-MSI revealed that large areas of the surface as well as subsurface channels compose primarily of the drug as presented in Fig. 9. A relatively homogeneous distribution of the drug in the polymer matrix could be achieved. The elution occurred from the drug-rich surface region. The third study deals with the characterization of a spin-coated poly(bisphenol-A-decane ether) film, in which it could be demonstrated that the interior surface pattern is hollow instead of solid and that it was located between two polymer layers rather than sitting on the substrate. Even though there is

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Different instruments to perform MALDI-MSI are currently on the market, which enhanced the field tremendously. Therefore, most users are limited to the proprietary software supplied by the vendors. (For more detailed information on the different software available please refer to Ref. [73].) To overcome these circumstances and to allow an easier comparison of data compared from different mass spectrometers, the dataformat imzML has been introduced [74], which enables the user to apply the best processing software suited for a specific question or application. Hence, recent developed software packages are supporting now this new universal format, as e.g., the automatic processing software of mass spectrometric images by Paschke et al. [75]. 4. Conclusion and future prospects

Fig. 9. 3D-SIMS-MSI analysis of one-hour elution time of sirolismus in a PLGA matrix. The overlay of the isosurface of a fragment ion of sirolismus (red), PLGA (green) and Na+ ion (purple) is shown in a (A) surface, (B) side, and (C) surface view. (For interpretation of the references to color in this figure caption, the reader is referred to the web version of the article.) Adapted from [71] with permission from the American Chemical Society.

a substantial number of 3D-SIMS-MSI studies on polymer surfaces as presented, 3D-MALDI-MSI has not yet been applied in polymer science. This is quite surprising since the first application on biological tissue was already 2005 [72]. Maybe the reason is the required slicing of the polymer film instead of the depth profiling capabilities of SIMS.

A variety of mass spectrometric imaging studies employing SIMS and MALDI on polymer surfaces have been presented in this contribution. Not all approaches have been introduced; however, a good overview has been aimed for. Future directions will certainly be on the MALDI-MSI approach since this ionization technique is newer and applications, which have already performed by SIMSMSI, are still waiting to be performed by MALDI-MSI, e.g., the analysis of blends and the investigation of stent coatings. In order to gain more information, complementary imaging techniques will be correlated and certainly even new instruments will be built to correlate these image modalities. One very important aspect of the imaging techniques is the possibility to quantify. This inheres a wide range of challenges as described recently [76], in particular the application of the internal standard. For the pharmaceutical industry the quantification of a drug and their metabolites in single or multiple organs is of high interest and, therefore, first approaches have been developed [77], e.g., employing a new software tool [78], or using a normalization factor [79]. In the polymer field a primary approach has as well been introduced just a while ago [80]. A series of additives of polymers have been quantified by MALDI-MSI using a solid sample preparation technique. However, additional future applications are still in progress. Additionally, 3D-MSI will be advanced in the future and presumably correlated with other 3D imaging techniques, such as MRI in the medical field. Even new soft ionization techniques, such as desorption electrospray ionization (DESI), which has already been proven valuable for the polymer analysis [81,82], or laserspray ionization (LSI), which has shown to be suitable for the MSI analysis of biological tissue using a commercial intermediate pressure MALDI ion mobility mass spectrometer [83], will be introduced in the future for approaching the imaging analysis of polymer surfaces. The high-mass resolving power of Fourier-transform (FT) mass spectrometers, the ability to perform accurate mass measurements, and the capability for tandem MS analysis (MSn ), which are beneficial for the analysis of polymers [84], will certainly as well be introduced for their MSI determination in the future. Another prospective direction will be the improvement of the spatial resolution. Currently, cellular resolution can be achieved on biological tissue [10,85] by reducing the laser spot size, which will be implemented sooner or later in the MSI analysis of synthetic polymers, too. An alternative approach to reduce the spatial resolution is to perform oversampling as demonstrated for the first time by the Sweedler group in 2005 [86]. Significant efforts have been conducted to perform atmospheric pressure (AP) MALDI-MSI using either a UV [87] or an IR laser [88] in biological applications and will of course be of interest for the analysis of polymer surfaces. Acknowledgements Financial support of the DFG (grant no. EG 102/4-1) and the Thüringer Kultusministerium (grant no. B515-07008) are

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