RAMAN SPECTROSCOPY FOR ADVANCED POLYMERIC

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RAMAN SPECTROSCOPY FOR ADVANCED POLYMERIC BIOMATERIALS Garima Agrawal, and Sangram K. Samal ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b00258 • Publication Date (Web): 09 Mar 2018 Downloaded from http://pubs.acs.org on March 9, 2018

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ACS Biomaterials Science & Engineering

RAMAN SPECTROSCOPY FOR ADVANCED POLYMERIC BIOMATERIALS Garima Agrawala*, Sangram K. Samalb a

Department of Polymer and Process Engineering, Indian Institute of Technology Roorkee,

Saharanpur Campus, Paper Mill Road, Saharanpur- 247 001, Uttar Pradesh, India * Email: [email protected] b

Materials Research Centre, Indian Institute of Science, Bangalore- 560 012, India

1.

Introduction

2.

Basic principles and instrumentation

3.

Raman characterization of polymer based drug delivery systems 3.1.

Polymer/drug solid dispersions, process parameters and drug dissolution

3.2.

Polymeric coatings for drug release

3.3.

Polymeric micro/nanoparticles for drug release and drug detection

4.

Raman characterization of polymeric biomaterials for tissue engineering

5.

Raman spectroscopy for biosensors

6.

Future perspectives and challenges

7.

Conclusions Acknowledgements References

Abstract In recent years, polymeric biomaterials have emerged as a potential candidate for therapeutic applications owing to their salient features. The characterization of these drugs and bioactive molecules loaded polymer based biomaterials is an important prerequisite for obtaining a deep understanding of their physicochemical behavior in order to ensure their successful clinical use. There are a variety of complementary characterization techniques available for the characterization of the biomaterials. This review highlights the potential of Raman spectroscopy 1

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including its importance for investigating the molecular structure of polymeric materials along with a brief description of its principles, instrumentation and recent advances. Keywords: polymer, biomaterial, therapeutic, characterization, Raman 1. Introduction In recent years, increasing attention has been paid to the synthesis and applications of polymer based biomaterials.1-3 Tailor made chemical structure, biocompatibility, degradability under biological environment and ease of chemical functionalization are some of the salient features that render polymers as potential candidate for designing biomaterials for both fundamental research and practical clinical applications.4-8 Polymers not only provide excellent support to the loaded drug and other biological molecules, but also control the kinetics of their release into the surrounding medium.9-10 In order to be successful for clinical applications, polymer based biomaterials are required to undergo different biological environment and exhibit desired cell interaction along with the body clearance of the degraded polymer which in turn depends on the molecular and structural properties of these materials.11-13 Hence, to obtain a deep insight into the physicochemical behavior of these polymeric materials, a variety of complementary characterization techniques have been employed which help us to understand the structure property relationship and further optimize these biomaterials for the complex biological requirements for therapeutic applications.14-16 These techniques include NMR, FTIR, Raman, Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy, X-ray diffraction (XRD), Electron Spectroscopy for Chemical Analysis (ESCA) and Differential Scanning Calorimetry (DSC) etc.17-22 Among these methods, AFM, SEM and TEM analysis are used for the morphological characterization while the amorphous or crystalline structure as well as impurity of the polymeric biomaterials is determined by ESCA, XRD, and DSC. On the other hand, the spectroscopic techniques provide us the better understanding of molecular structure and component dynamics of the materials.23 They provide us with deep insight of individual component and its interaction with other same/different components.24 Further, these techniques are noninvasive and hence allow long term study of desired site.25 Hence, these versatile characterization techniques are well suited to address many biomaterial related challenges by facilitating the designing of materials with required properties. 2


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IR spectroscopy measures the transitions in the low energy infrared region of the electromagnetic spectrum while Raman measurements are carried out using UV, visible or near IR sources, thus avoiding the need for sample mounting in potassium bromide pellet or on calcium fluoride windows as required for FTIR. Although both IR and Raman provide good details in the fingerprint region, yet many functional groups such as amino acid residues, S–S disulfide bridges, aromatic bonds, C–S linkages from proteins, and nucleic acid signals etc. are more highlighted in Raman spectrum compared to IR which shows broad features due to overlapping bands.26 This is advantageous for diagnostic application such as differentiation between normal and cancerous tissue. Minimal interference from the highly polar water vibrations as compared to IR spectroscopy combined with low cost, ease of use, and non-destructive characteristic makes Raman spectroscopy a potential method for the in vivo characterization of biomaterials and cell activity in scaffolds. It can be used for the analysis of biomaterials based drug delivery systems, cell viability, cell differentiation, mitosis, mineralization, and cell death etc. in real time. However, Raman spectroscopy suffers with the issue of low signal sensitivity, sample fluorescence, sample heating and damage by the laser beam etc. In case of photo-damage, a photoexcited species transfers its energy to oxygen molecule which in turn in its singlet state attacks the donating species and thus leads to the bond cleavage. Additionally, high power density and absorption are also responsible to cause thermal damage. Recently, these problems have been addressed by several technical modifications in the instrumentation. The main aim of this review is to provide the readers a brief overview of general principle and instrumentation of Raman spectroscopy, its limitations and potential of Fourier-transform Raman spectroscopy for the characterization of polymeric biomaterials.

2. Basic principles and instrumentation Raman spectroscopy is a scattering technique based on the interaction of incident beam with the vibrating molecules in the sample (Figure 1A).27 Here, the sample is illuminated with monochromatic light, generally in the near-infrared, visible or UV range.28 When the incident radiation strikes the sample, mostly elastic scattering occurs where scattered radiation has a frequency similar to that of incident beam (Figure 1B).29 This elastic scattering is also known as 3



Rayleigh scattering.30 On the other hand, when the incident beam interacts with vibrational modes associated with chemical bonds of the molecules, the resulting scattered radiation has different frequency compared to incident beam (Figure 1B). This inelastic scattering is also known as Raman scattering. When the incident photon loses its energy to the vibrating bonds of the molecules, stokes lines appear in Raman spectrum and the molecule ends up in higher energy state. However, when the scattered photon has higher energy than the incident photon, antistokes lines are generated in the spectrum.23 The population of molecules existing in the excited vibrational state is much less than that in the ground state at ambient temperature, and hence the intensity of the Stokes lines is higher than that of the anti-Stokes lines. In general, only Stokes lines are employed in Raman spectrum.31-33 Scattered photons are generally collected at right angle to incident photons.

Figure 1. Schematic diagram showing: (A) light scattering when the sample is exposed to laser. Reproduced with permission from ref 28. Copyright 2016 Springer Nature. (B) energy transitions involved in Rayleigh scattering and Raman scattering. Reproduced with permission from ref 29. Copyright 2014 MDPI AG. A Raman spectrum is presented in the range of 400–4,000 cm−1 wavenumbers as an intensityversus wavelength shift. Raman spectroscopy provides “molecular fingerprint” as every molecule possess a distinct set of chemical bonds which leads to characteristic vibrational

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modes. Hence, Raman spectroscopy has been an important tool for the analysis of proteins, lipids, carbohydrates, phosphate groups of DNA etc.34 In Raman spectrometer various laser sources such as Argon ion laser (488 and 514.5 nm), Krypton ion laser (530.9 and 647.1 nm), Helium–Neon (He–Ne) (632.8 nm), Near Infrared diode lasers (785 and 830 nm), Neodymium–Yttrium Aluminum Garnet (Nd:YAG) and Neodymium– Yttrium Ortho-Vanadate (Nd:YVO4) (1064 nm) and frequency doubled Nd:YAG and Nd:YVO4 diode lasers (532 nm) are used to provide stable and intense beam of radiation.35 Laser sources with lower wavelength such as Argon ion laser, Krypton ion laser can cause photoabalation of the sample along with strong fluorescence. This is overcome by the laser sources with higher wavelength such as Nd:YAG lasers.32 Further, holographic filters, edge filters, notch filters, high-throughput optics, grating monochromators, rejection filters are used to separate less intense Raman lines from strong Rayleigh scattering.36-37 Charge transfer devices (CTDs) such as charge-coupled devices (CCDs) and charge-injection devices (CIDs) are used as sensitive detectors which convert the incoming optical signal into charge and transferred to readout devices.23 Extracting the useful information from the extensive computer data is a major challenge. In this regard, both univariate analysis and multivariate analysis are used for processing the data. Univariate analysis is the easiest and most prevelant data analysis approach and it can provide sufficient information in many cases.38 Multivariate analysis include various approaches to analyze the data including principal component analysis (PCA), partial least square regression (PLS), classical least squares (CLS), multivariate curve resolution (MCR) and partial least square discriminant analysis (PLS-DA).39 Here, it is essential to validate preprocessing, selection of variables and model in order to obtain reliable quantitative information.40-44 Raman and infrared (IR) spectroscopy are complementary vibrational spectroscopic techniques and are associated with the measurement of vibrational and rotational energy changes.25, 45-47 The primary requirement for a molecule to be Raman active is the change in its polarity upon excitement with radiation while IR requires the change in molecular dipole moment.48 Hence, it is not possible to obtain any spectroscopic information for homonuclear molecules using Raman technique. In general, a Raman spectrum is significantly simpler

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compared to its IR counterpart as overtones, combination and difference bands are rare in Raman. Conventional Raman spectroscopic technique used for polymer analysis encounters the problem of laser induced background fluorescence, long spectral acquisition time and photodecomposition of visible light sensitive sample upon long exposure.17, 49 Sample burning also known as photoablation can be observed both visually and spectroscopically as localized dark areas on the sample and by the presence of peak at ~1,500 cm−1 corresponding to amorphous carbon bands in the spectra respectively.28 Saturation of the detector is another indication of local thermal decomposition of the sample especially when UV or visible wavelengths are used. In order to overcome these limitations Fourier Transform-Raman spectrophotometers

(FT-Raman)

were

introduced

in

late

1980’s.45,

50

FT-Raman

spectrophotometer comprises of a near infrared laser as the excitation source such as Nd–YAG which emits the radiation at 1064 nm.51 A Michelson interferometer is used along with InGaAs and germanium (Ge) detectors operating at cryogenic temperatures or under thermoelectric Peltier cooling so that the signal-to-noise ratio can be improved.52 At cryogenic temperature, the molecular motions become extremely slow and materials are in a highly ordered state, thus the noise is reduced.23 Further, Resonance Raman Spectroscopy (RRS) and Surface Enhanced Raman Spectroscopy (SERS) have been developed in order to overcome the low sensitivity due to weak Raman scattering.53-54 In RRS, the excitation frequency is chosen to overlap with an electronic transition in an area of UV-visible absorption. Such a frequency match results into significantly improved detection limits, reduced measurement time along with intensity increment by factors of 102-106.55 However, significant fluorescence background creates problem in spectrum analysis. Alternatively, intensity of Raman signals is improved by SERS technique SERS technique which involves the sample absorption on a colloidal metallic surface (silver, gold or copper) or by nanostructures such as plasmonic-magnetic silica nanotubes. 27, 56-57 This also helps in overcoming the limitation of fluorescence background caused by cutting agents, diluents and matrices.56, 58 Further, the Raman signal can be amplified up to ten orders of magnitude and the signal enhancement is achieved by the combination of electric field of structured surface and the coincidence of the laser wavelength with an optical absorption of the compound of interest. This 6


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effect is known as Surface Enhanced Resonance Raman scattering, (SERRS).59-60 Although the above mentioned modifications of Raman spectroscopy are extremely powerful in their own particular way, yet their routine use for biomedical application is still limited due to their increased technical complexity. Raman microspectroscopy is one of the most exciting developments in recent years. Here, a Raman spectrometer is integrated with an optical microscope, thus enabling both visual and spectroscopic examinations of the sample.28 The advantage of this technique is that very less amount of sample is required and the desired small area within a sample can be investigated visually. Coupling of Raman spectroscopy with optical microscopy has opened the new doors for biomedical applications such as noninvasive characterization of biological materials.61-62

3. Raman characterization of polymer based drug delivery systems 3.1. Polymer/drug solid dispersions, process parameters and drug dissolution Raman spectroscopy has often been used for gaining non-invasive insight on the drugs loaded inside the polymer matrix based on the characteristic peaks of specific chemical units within the drug molecule.63-65 Some molecules can exist in two or more polymorphic forms having different physical and chemical properties. This ultimately affects the quality of the finished pharmaceutical product in terms of drug dissolution, stability and bioavailability. Hence, it is very important to detect and quantify the polymorphic forms in mixtures. Analysis of polymorphs by using XRD, NMR, FT-IR is difficult as the active ingredients such as diluents present in the tablet interfere with the measurements. Additionally, non-aromatic, hydrophilic excipients exhibit poor Raman scattering in contrast to aromatic, hydrophobic drugs which show characteristic peaks in Raman spectra even if present in small amount. Amorphous compounds exhibit broad bands in Raman spectra as compared to crystalline forms due to the existence of less structured vibrational environments within the sample. Furuyama et al. employed Raman mapping for the evaluation of the solid dispersions of troglitazone- polyvinylpyrrolidone (PVP) which consists of two crystalline diastereomer-pairs, RR/SS (Raman band at 1730 cm−1), RS/SR (1685 cm−1) and amorphous phase at 1747 cm−1.66 Solid dispersions with various crystallinities were prepared by closed melting method. Based on the experimental results, it was evaluated that

7



mostly amorphous troglitazone co-existed in the rubbery phase of PVP and the amount of crystalline RR/SS was less in PVP compared to RS/SR form.66 Calvo et al. used Raman spectroscopy coupled to multivariate analysis in order to determine the main form of albendazole in bulk drug. Albendazole exists in two polymorphic forms: a) form I which is metastable crystal at room temperature; b) form II, the stable one but less water soluble compared to form I. The differences observed in the IR spectra of both forms were insufficient and XRD was not good enough as it provided consistent results only when coupled with DSC and TG/DTG. Hence, the Raman spectra of albendazole were measured with a Thermo Scientific DXR Raman microscope having solid state laser of 532 nm, a confocal aperture of 25 µm pinhole, and a 10x objective.67 Comparison of Raman spectra of these two forms showed the presence of a peak at 1361 cm−1 corresponding to form II while a shoulder at 1324 cm−1 was characteristic of Form I (Figure 2). Further, peaks at 900. 866, 769 and 756 cm−1 are observed in case of Form II, while Form I exhibited two small overlapped peaks at 866 and 855 cm−1 along with a single peak at 764 cm−1. The experimental results indicated that solid-state form I was in abundance in albendazole bulk drug.67

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Figure 2. Raman spectra of the solid-state forms of albendazole, Form I (—) and Form II (---) (A). Zoom in Raman spectra in the area of 1396–1280 cm−1 (B). Reproduced with permission from ref 67. Copyright 2016 Elsevier.

Vajna et al. employed Raman spectroscopy with multivariate curve resolution alternating least squares to analyze the difference in composition and the distribution of the constituents in verapamil formulations prepared by wet granulation and melt extrusion.68 Almeida et al. used Raman mapping with peak area analysis to assess size of polyethylene oxide crystal domains in the formulation of metoprolol tartrate, polyethylene oxide and ethylene vinyl acetate with varying levels of vinyl acetate prepared by hot melt extrusion.69 Van Renterghem et al. used in-line Raman spectroscopy for analyzing the effect of process parameters on solid state transformation of Eudragit® RS PO polymer and Metoprolol tartrate drug during mixing in a pharmaceutical mini hot melt extrusion process. As shown in figure 3, an in line Raman dynisco probe was employed which was connected via a fiber optical cable to the Rxn2 Raman spectrometer having excitation source at 785 nm and CCD detector. Raman spectra were collected every 5 s with an acquisition time of 3 s for a duration of 15 min and were analyzed using Simca 13.0.3.70 Raman bands at 819 cm−1 and 847 cm−1 due to out of plane vibrations of COOH groups of crystalline MPT and at 812 cm−1 for C-C stretching vibration of Eudragit® RS PO were used for analysis.71-72 It was observed that processing the sample above the melting point of the drug resulted into the amorphous drug whereas processing below the drug melting point produced solid dispersions with partially amorphous/crystalline drug. Further, Saerens et al. employed in-line Raman spectroscopy for the determination of the solid state of Celecoxib (CEL) in Eudragit® E PO formulation during hot melt extrusion.73 Additionally, experimental results indicated that off line analysis by XRD and DSC were insufficient to detect the presence of small amount of crystalline celecoxib which further induced recrystallization of celecoxib during extrudate storage which could be observed by Raman spectroscopy successfully.

9



Figure 3. Pharma micro extruder with three different areas for the Raman Dynisco probe: (1) in the extruder die (2) lowest position against the screws (3) highest position against the screws. Reproduced with permission from ref 70. Copyright 2017 Elsevier.

Puncochova et al. investigated the release mechanism of hydrophobic drug aprepitant from amorphous solid dispersion based on either amphiphilic copolymer Soluplus® or hydrophilic polyvinylpyrrolidone (PVP) using a WITec alpha 300R+ confocal Raman microscope (WITec GmbH, Ulm, Germany) at an excitation wavelength of 785 nm with an integration time of 0.5 s.74 Characteristic bands at 1005 cm−1, 1047 cm−1, 1450 cm−1 and 935 cm−1 were observed corresponding to amorphous drug, crystalline drug, Soluplus and PVP respectively (Figure 4). It was observed by Raman microscopy that although both the polymers had amorphous phase of the drug loaded before dissolution, yet only Soluplus could retain this form of the drug due to its amphiphilic character. On the other hand, drug crystals are formed in PVP tablet over the period of time as PVP continues to dissolve rapidly due to its hydrophilic character.

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Figure 4. Raman spectra of amorphous aprepitant, crystalline aprepitant, Soluplus and PVP. Reproduced with permission from ref 74. Copyright 2016 Elsevier. Raman signals below 100 cm-1 are blocked even by the narrowest edge filters used for blocking out the Rayleigh backscatter from the excitation laser and thus ultralow frequency Raman spectroscopy has been overlooked for long time.75 Development in the area of ultranarrow band filters and wavelength-stabilized lasers in recent years has led to increased attention on ultralow frequency terahertz-Raman or “THz-Raman” domain which provides useful information regarding the structural analysis of the sample.76 THz Raman exhibit molecular transitions and vibrations in the range from 5 cm-1 to 200 cm-1 and provides important structural details including lattice or polymer structures, crystal orientation, spin waves, and phonon modes.76-79 THz Raman signals improve overall Raman intensity and signal to noise ratio. Additionally, the incorporation of anti-Stokes signals provides confirmation of Stokes peaks, thus providing an inherent self-calibration. Tres et al. used low frequency Raman spectroscopy to investigate the dissolution mechanisms of hydrophobic felodipine in a polymeric matrix of copovidone VA64.80 The spectra of raw materials show that the drug has sharp bands while less defined bands are observed in case of copovidone. Comparison of melt quenched felodipine (amorphous) and commercially received crystalline felodipine shows that the bands of the crystalline form appear more intense and sharper (Figure 5a,b).

80

Raman data of the 50% drug loaded polymer matrix

over the period of time showed that amorphous felodipine crystallizes at different rates in different regions of the compact surface due to the faster dissolution of copovidone. A 11



comparison to melt quenched felodipine shows that the bands at 1202, 1484 and 1642 cm− 1 shift to lower wavenumber and they become more intense and sharper which is the characteristic of crystalline form (Figure 5c). Additionally, well-defined bands appear at 94 and 168 cm− 1 confirming that amorphous felodipine begins to re-crystallize by this time-point (Figure 5d).80

Figure 5. Finger print (a) and phonon-mode (b) regions of Raman spectra of various raw materials; finger print (c) and phonon-mode (d) regions of Raman spectra relative to the dissolution of the 50% extrudate compact, with reference spectra in red. Reproduced with permission from ref 80. Copyright 2014 Elsevier.

3.2. Polymeric coatings for drug release Drug eluting coatings, a combination of polymer and drug, are applied to biological implants in order to control the release of drug at the target site. Antimicrobials eluting catheters, pacemakers with steroids, and stents having sirolimus, paclitaxel or zotarolimus eluting coatings 12


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are some of the examples in this area.81-82 CYPHER Sirolimus-eluting Coronary Stents and the TAXUS Express are two commercially available products where the eluted drug helps to prevent the scar like tissue growth through the stent.83 In recent years, Raman spectroscopy has been used as an essential tool for understanding drug/polymer composition, drug distribution inside the polymer matrix, thickness of drug containing coating and kinetics of drug release.84-87 Further, confocal Raman microscopy is advantageous here as it provides the possibility of in vivo analysis with a real-time evaluation of drug permeation mechanisms. Belu et al. used confocal Raman microscopy to analyze the surface and the interior of rapamycin containing poly(lactic-co-glycolic acid) (PLGA) coatings.81 The stent coatings were soaked in buffer and the diffusion of rapamycin was visualized. Measurements were done using WITec CRM 200 scanning confocal Raman microscope (Ulm, Germany) equipped with a NiYAG laser operating at 532 nm in Raman imaging mode and the integration time was 0.3 s. Experimental results indicated that the distribution of rapamycin inside the coating was homogeneous upto 25 wt% loading while non-uniform distribution was observed for higher concentration. Further, polyhydroxyethyl cellulose (HEC) films containing Au nanoparticles were developed by Lee et al. for the detection of therapeutic drug phenytoin in the range of 1020 mg/L.88 A good correlation was observed between the phenytoin concentration and the SERS signal of phenytoin at 1004 cm-1 (Figure 6).

13



Figure 6. SERS spectra obtained with Au aggregates containing Poly-HEC films of 15 µL droplets of 1x10−3 mol/dm3 phenytoin in (a) water and (b) PBS. Reproduced with permission from ref 88. Copyright 2016 Elsevier.

Balss et al. used confocal Raman microscopy with multivariate analysis to investigate the spatial distribution of the components in CYPHER Sirolimus-eluting coronary Stents quantitatively.85 A discrete layer of poly(o-chloro-p-xylylene) (parylene-C) was deposited onto stainless steel stents before doing the spray coating of solutions containing sirolimus, poly(ethylene-co-vinyl acetate) (PEVA), and poly(n-butyl methacrylate) (PBMA). CRM200 microscope system from WITec Instruments Corporation (Savoy, IL) equipped with a Nd:YAG laser (532 nm), a single monochromator, CCD camera, a holographic laser bandpass rejection filter to minimize Rayleigh scattering was used for the measurements. The parylene-C signal between 1265-1365 cm-1 was used to distinguish pixels of drug/polymer layer and parylene-C layer The calibration curves for sirolimus, PBMA, and PEVA were developed by employing partial least square models which were found to have better accuracy than the univariate models.84-85 Analysis of each pixel showed that PEVA rich regions were close to parylene-C layer while sirolimus rich regions were close to coating–air interface.85 Further, Biggs et al. investigated the release of sirolimus in correlation with pore formation, pore throats, and pore networks present in the polymer matrix of PEVA and PVMA.89 Surface and subsurface Raman images before drug elution showed the inhomogeneous distribution of drug (orange) and polymer (blue) along with continuous networks in the micrometer range (Figure 7). Over the period of drug release, it was found that the voids created after drug release was reconstituted and the polymer matrix was rearranged.

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Figure 7. Raman spectra of sirolimus, PEVA/PBMA, and parylene-C (left). Confocal Raman mocroscope images of the CYPHER stent coating at 0 h elution (right). “Depth (xz)” refers to a cross section in the xz plane of the sample. “Surface (xy)” and “Subsurface (xy)” were acquired in two different xy planes of the sample. Dashed lines corresponds to the intersection of the xz and xy image planes. Reproduced with permission from ref 89. Copyright 2012 American Chemical Society.

Dong et al. used confocal Raman microscopy for real-time release of the drug rapamycin from arborescent polyisobutylene-block-polystyrene (arbIBS) thin films after swelling in phosphate buffer.90 Here, Witec alpha 300R confocal Raman microscope equipped with Ar ion laser (514.5 nm) and 50-mW maximum output power, 100x air objective and a 100x water immersion objective was used for imaging. Characteristic peaks of rapamycin at 1630 cm-1 (C=O stretching), and of arbIBS around 3060 cm-1 (aromatic C-H stretching) and 1000 cm-1 (benzene ring breathing) were employed for developing Raman images. Experimental results exhibited that arbIBS forms a continuous matrix while rapamycin is mostly present as discrete micronsized domains along with smaller concentration evenly distributed throughout the arbIBS matrix.

3.3. Polymeric micro/nanoparticles for drug release and drug detection

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In recent years, polymer based microparticles have gained significant interest for therapeutic applications.91-95 Raman spectroscopic tools have been successfully used for the characterization of microparticles, drug and active biomolecules loaded inside the microparticles, and the release of drug.7, 96-99 Apeldoorn et al. performed Raman imaging for investigating the degradation of Poly(lactic-co-glycolic acid) (PLGA) microspheres inside macrophages.100 Approximately 30% reduction in the intensity of ester bond peak at 1768 cm-1 was observed 2 weeks after phagocytosis. Additionally, the peaks at 1004 cm-1 (phenylalanine), 1662 cm-1 (amide I) and 1440 cm-1 (CH2 groups in lipids) indicated the presence of both proteins and lipids in the voids created after microsphere degradation. Based on the experimental results it was reported that concentric cavities are formed in the microspheres during degradation and probably proteins and lipids travel through one or more pores. Widjaja et al. investigated the spatial distribution of PLGA, poly(l-lactide) (PLLA), and poly(ε-caprolactone) (PCL) in double-walled microsphere using Raman mapping with bandtarget entropy minimization (BTEM) analysis.101 The measurements also revealed the presence of semicrystalline polyglycolic acid (PGA) which is a decomposition product of PLGA, and dichloromethane (DCM) which was used as a solvent for the microparticles preparation. Copperphthalocyanine blue, and calcite, were found as unexpected contaminants inside the particles. Doub et al. investigated the aqueous suspension nasal spray formulations using Raman method in order to establish chemical identity, particle size and particle size distribution (PSD) of ingredient specific components.102 The components included beclomethasone dipropionate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC), dextrose, benzalkonium chloride, polysorbate 80 and phenylethyl alcohol which could be clearly discriminated in the formulated sample based on their characteristic Raman spectrum.102 Rizi et al. fabricated pH responsive Eudragit L100 and AQOAT AS-MG polymer based microparticles loaded with a hydrophobic drug (hydrocortisone) by spray drying method. Raman mapping with univariate analysis showed that hydrocortisone was homogeneously distributed inside the microparticles when the saturation limit for the drug loading is not reached.103 Sievens-Figueroa et al. developed hydroxyl propyl methyl cellulose based films containing Biopharmaceutical Classification System (BCS) Class II drug nanoparticles.104 Raman spectra

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was used to investigate the crystalline or amorphous form of three different drugs namely naproxen (NPX), fenofibrate (FNB) and griseofulvin (GF) which were used in the formulations. Tian et al. synthesized gold nanostars conjugated with poly(ethylene glycol) (PEG) spacer having –SH and –COOH functional group which were in turn used for covalent binding of amine-containing anticancer drug mitoxantrone.105 This theranostic approach provided the possibility of real time tracking of drug release from nanocarriers both in vitro and in vivo. The results based on plasmonic-tunable Raman/FTIR imaging showed that drug delivery vehicles accumulated in the heart of healthy mice after 5 min of administration and infiltrated in the lung tumor site of unhealthy mice after 5 h of injection.105 Liu et al. prepared gold@silica based drug delivery system containing doxorubicin drug attached via pH labile hydrazone linkages. 106These nanocarriers showed capability of not only killing the cancer cells but also providing SERS tracing of intracellular details. Conde et al. fabricated α-Mercapto-ω-carboxy polyethylene glycol (PEG) entrapped gold nanoantennas with 3,3′-diethylthiatricarbocyaniniodid (DTTC) Raman reporter and FDA antibody–drug conjugate – Cetuximab, that specifically target epidermal growth factor receptors on human cancer cells (Figure 8).107 These composite particles are able to generate intense SERS signal at 508 cm− 1 with simultaneous inhibition of tumor growth.

Figure 8. Schematic representation of Antibody–drug gold SERS nanoantennas (a); Binding of nanoantennas with receptors on cancer cells leading to proliferation inhibition. Reproduced with permission from ref 107. Copyright 2014 Elsevier.

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Sundar et al. synthesized 3-aminopropyltriethoxy silane (APTES) modified magnaetite nanoparticles for the delivery of anticancer drug curcumin.108 Raman spectroscopy was eployed for investigating the structure of naked Fe3O4 and APTES coated Fe3O4nanoparticles. Raman peaks at 665 and 554 cm− 1 were characteristic of bulk phase Fe3O4. The presence of APTES on magnetite

surface

was

confirmed

by

peaks

in

the

range

of

1420 cm− 1 to

1480 cm− 1 corresponding to –CH vibrations. Romero et al. exploited the potential of Raman mapping to investigate the distribution of poly(ethylene imine) or bovine serum albumin stabilized PLGA nanoparticles into HepG2 cells.109 Based on the differences in the Raman spectra of lipid bodies, cytoplasm and nucleus it was reported that PLGA nanoparticles were mostly associated with lipid bodies. Two types of liposomal carrier systems namely plain DSPC-d70 liposomes (LIP) and cell penetrating TAT peptide-modified DSPC-d70 liposomes (TATp-LIP) were developed by Matthaeus et al. to deliver the biologically active compounds to their target site.110 Raman measurements exhibited that depending on the surface properties, there were different rates and efficiency for the uptake of both the type of carrier systems within human breast adenocarcinoma MCF-7 cells. Further, Han et al. generated Ag nanoparticles based colloidal superstructures in the aqueous phase using oil in water emulsion method.111 These superstructures were used as threedimensional SERS hotspots for quantitative analysis of methamphetamine and 3,4methylenedioxymethamphetamine in human urine. On the other hand, Dong et al. fabricated Methoxy–mercapto-poly(ethylene glycol) coated gold nanorods for direct detection of drugs such as methamphetamine and 3,4-methylenedioxymethamphetamine in body fluid combining with the portable Raman spectrometer exploiting SERS approach (Figure 9).112 This approach involved direct mixing of the suspected sample with gold nanorods colloidal dispersion which in turn is exposed onto a SERS chip. As a next step this chip was inserted into the sample slit of a portable spectrometer and identified by support vector machines (SVM). Finally, the test result was displayed and the entire process was quick making it highly practical for field applications.

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Figure 9. Schematic representation of dynamic surface-enhanced Raman spectroscopy (DSERS) and a classification algorithm called support vector machines (SVM) solution. Reproduced with permission from ref 112. Copyright 2015 American Chemical Society.

One of the biggest challenges for moving Raman spectroscopy technique from the laboratory use to the real clinical application for the health care providers is the high computational burden for extracting the useful information from the measurements. Hence, new computational techniques and analytical tools for signal processing need to be developed which are easy to understand and to be used by health care personnel for dealing with large amounts of real-time diagnostic data coming from living systems.

4. Raman characterization of polymeric biomaterials for tissue engineering Raman spectroscopy has proved to be a potential tool for characterizing the polymeric biomaterials designed especially for tissue engineering applications. Kunstar et al. analyzed the formation

of

extracellular

terephthalate)–poly(butylene

matrix

(ECM) in

terephthalate)

three-dimensional

(PEOT/PBT)

poly(ethylene

scaffolds

using

oxide Raman

−1

microspectroscopy. Raman bands at 937 and at 1062 cm , corresponding to collagen and sulfated glycosaminoglycans respectively, were used as Raman markers for ECM formation in scaffolds.113 Moreover, it was possible to collect the Raman signal from multiple pores using fiber optic Raman setup and thus giving an average signal present in tissue-engineered constructs. Fiber-optic Raman measurement was carried out using fibre-optic Raman probe which consisted of 50 collection fibres that were arranged into 10 branches. Laser illumination was achieved using a 300 µm core optical fibre that terminated in a stainless steel ferrule (outer diameter of 400 µm) and coupled to an 830 nm laser source.113

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Samal et al. employed Raman spectroscopy to investigate the structural properties of silk fibroin protein (SFP) scaffolds, before and after formation of apatitic minerals mediated by alkaline phosphatase (ALP) enzyme.114 FT-Raman spectra were collected on an FT-Raman Module (NXR, Thermo Fisher Scientific, Madison, WI, USA) equipped with a laser power of 0.35 W. The SFP scaffolds displayed characteristic bands at 1664, 1230, 1080 cm-1 corresponding to βsheets and relatively weak bands at 1261 cm-1 associated with α-helices. A strong peak at 960 cm-1 was observed in the Raman spectrum of enzymatically mineralized scaffolds which was absent in both native silk scaffolds and scaffolds without enzyme. Ku et al. fabricated a nanofibrous scaffold consisting of polycaprolactone (PCL) based core coated with poly(dopamine) (PDA) in order to impart the characteristics similar to mussel adhesives by exploiting numerous catechol moieties.115 Pure PCL fibers and gelatin coated PCL fibers were used as control in order to compare human endothelial cells attachment, proliferation, and phenotypic maintenance. In Raman spectra characteristic peaks of PCL were observed at 1727 cm-1 (νC=O), at 1421, 1444, and 1469 cm-1 (δCH2); at 1287, and 1308 cm-1 (ωCH2). PDA coating was confirmed with the help of peaks at 1345 and 1603cm-1 which correspond to the aromatic component of PDA (Figure 10c). The PDA modification was further confirmed via contact angle measurements which showed changes in the surface properties of fibers from hydrophobic to hydrophilic nature (Figure 10d).115 It was observed that PDA coated fibers exhibited enhanced cell adhesion and viability along with positive expression of PECAM-1 and vWF known as endothelial cell markers.

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Figure 10. Schematic illustration of cell adhesion on PDA-coated PCL nanofibers (PCL NFs) (A); SEM images (B); Raman spectra (C), and water contact angle measurement (D) of unmodified, gelatin-coated, and PDA-coated PCL NFs. Reproduced with permission from ref 115. Copyright 2010 Elsevier. 21



Pielesz et al. reported the use of Raman spectroscopy for analyzing the diffusion properties of model azo dyes within Ca-alginate/carboxymethylcellulose (Medisorb A) wound dressing.116 Raman spectra of alginates immersed in Ringer’s solution showed peak shifts along with the appearance of new bands as the sodium content increased. The change in the atomic weight of cation due to the replacement of calcium ions results into the change in environment around the carbonyl group and hence the peak shift occurs. New peaks were observed at 1034–1016 and 850 cm−1 regions in the spectra after the release process, thus showing the potential of Raman technique to gain a deep insight on the diffusion properties of active pharmaceutical ingredients.116 Taking advantage of the tolerance of Raman spectroscopy to water, this technique has been used to characterize various hydrogels systems developed for tissue engineering applications.117-120 Douglas et al designed gellan gum based hydrogels containing calcium and magnesium phosphate minerals in order to enhance the interaction with surrounding bone medium after implantation. The mineralization was confirmed by the presence of characteristic peaks of PO43- (960 cm−1) and HPO42- (1010 cm−1) in Raman spectra.121 Similarly, the mineralization in chitosan based hydrogels developed to study osteogenic cell study was followed by Dash et al using Raman spectroscopy.122 Here, P–O stretch band at 980–985 cm−1 indicated the presence of acid calcium phosphate phases such as brushite. Monitoring the in vitro growth of the tissue noninvasively is a prime requisite in order to achieve the successful use of developed tissue engineering products and simultaneously reducing the number of animals used. Currently the performance of these scaffolds is analyzed by conventional destructive methods such as histological analysis.123 The conventional Raman spectroscopy is also limited to the analysis of the interaction of cells and materials on the surface of the scaffolds. In order to address this, spatially offset Raman spectroscopy (SORS) has been recently developed which allows us to retrieve the subsurface chemical information typically from depths of 20 µm to 5 mm range, which is beyond the reach of confocal Raman spectroscopy.124-126 SORS relies on the collection of Raman spectra at different points which are spatially distant from the point of laser incidence followed by scaled subtraction of the two measurements representing the subsurface and surface spectra in case of two layer system and multivariate data analysis for multilayered biological samples.127-128 Measurements performed at 22


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different points represent the contributions from different layers present at different depths in the sample. The signal from deeper layer is spread wider compared to the shallow layers due to the sideways diffusion of the photos originating from deeper layers as they have to cover larger distance. It is noteworthy that SORS is capable of not only suppressing the Raman signal but also the interfering fluorescence signal originating from surface layer. This helps in in vivo spectroscopy where melanin present in the skin leads to high fluorescence and needs to be avoided. This approach has been further used for various applications such as investigating the bones at suitable depth from skin, identification and analysis of calcifications in breast cancer lesions, and probing of capsules or coated tablets through their coating etc.129-132 The major limitation of conventional SORS method stems from the collection of multiple spectra on different CCDs. Hence, small variations due to imaging imperfections in any spectra lead to artifact in processed spectra and thus limiting its sensitivity. The biomedical use of this approach is further restricted due to long acquisition time which is not possible in many cases due to the inability of the patient to stay still. Additionally, the possibility of enhancing the incident laser power to improve the signal is also restricted due to the possible photo-damage of the tissue and the associated safety levels.

5. Raman spectroscopy for biosensors In recent years, increasing attention has been paid to develop sustainable and safe biosensors for the detection of desired biological indicators in order to improve the patients’ quality of life. However, identification of the desired indicator present in ultrasmall amount in a complex biological environment and assessment of its effect poses significant challenges in developing new biosensors. Diabetes is one of the most significant medical problems and the patients are required to frequently check their blood sugar level. To improve the quality of life for the people suffering with Diabetes is driving the research for developing in vivo glucose sensor for real time analysis of glucose levels and thus avoiding the need of drawing blood samples every time. Raman spectroscopy can easily differentiate between galactose and glucose but it lacks the sensitivity required for the real time rapid measurements of glucose concentration in blood.133 To achieve this, longer acquisition time and higher laser power would be required which is not suitable for biological environment. To overcome this limitation, glucose biosensor based on 23



SERS has been developed by Van Duyne et al. SERS active surface was developed by depositing a silver film on closely packed polystyrene nanospheres (AgFON). This surface was further functionalized with alkanethiol monolayer and the experimental results indicated that the developed sensor could detect glucose concentrations even in the presence of additional bioanalytes.134 The developed SERS based sensor was further combined with spatially offset Raman spectroscopy (SORS), resulting in surface enhanced SORS (SESORS).135 This modified sensor allowed the measurement of glucose level through the skin of living rats with high accuracy and consistency. Glucose concentration even less than the currently accepted lower limit established by the International Organization Standard requirements could be measured and thus opening a new pathway for the welfare of diabetic patients. In the quest of developing highly sensitive and selective biosensors, SERS has emerged as a potential tool for the investigation of biological samples and diseases such as cancer, Alzheimer’s disease, and Parkinson’s disease.136-138 For example, a hand held spectroscopic device “SpectroPen” has been developed by Mohs et al. for real-time tumor detection and imageguided surgery.137 This Spectropen works by using pegylated colloidal gold as surface-enhanced Raman scattering (SERS) contrast agent and thus exhibit higher detection sensitivity and more consistent tumor signals than the ones obtained by native fluorescence or normal Raman scattering. SERS based sensors to detect proteins, DNA, illegal dyes and foreign proteins in food, and reagent less aptameric sensor to detect cocaine have also been reported in the literature.139-141 For common SERS substrates consisting of Ag and Au, measurements are performed in near IR and visible region. However there is a huge scope of technical advancements in the direction of using deep UV as it will be helpful for the detection of many biological molecules which have electronic resonances in this wavelength range, resulting in both electronic resonance and SERS enhancements. In order to achieve this aim, especial attention should be paid to develop suitable plasmonic material, to avoid photodegradation of sample, to increase the efficiency of optical filaments and CCDs. For successful use of SERS in routine analysis, the reproducibility of nanostructured surface and hence SERS measurements need to ensured and special focus should be given to the following points: i) the nanoparticles should be arranged in a regular pattern and the SERS substrate formation should be reproducible from batch to batch; ii) 24


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ease of preparation and low cost; iii) the substrate should be stable in long term and should provide significant signal enhancement; iv) signal enhancement across the surface should be homogeneous; v) the substrate should be biocompatible when it is intended to be used for biomedical applications. Recently, increasing attention has been paid to develop tip-enhanced Raman spectroscopy (TERS) which is a combination of SERS spectroscopy with atomic force microscopy (AFM). This technique uses metallic probes for scanning the sample surface and a laser beam is focused at the apex of the tip. TERS measurements are done by modifying an AFM with optical excitation and collection optics. Highly selective SERS spectra are obtained using the optimum measurement conditions along with acquiring the topographical information of the sample. TERS measurements have been performed for analyzing both inorganic and organic analytes such as bucky balls,142 carbon nanotubes,143 dye molecules and dye sensitized solar cells144 etc. This technique has been further extended to achieve better understanding of biological samples such as distinguishing different components and domains on biological surfaces,145-146 discrimination of diverse viruses based on their nano-fingerprint information,147 characterization of single stranded RNA148 and hydrogen bonding in DNA bases149 etc. One of the main focus issues in TERS is the development of TERS tips with stable and reproducible field enhancement. It is extremely important to have reliable information about the intrinsic resolution and enhancement factor in TERS. Development of novel tip designing strategies is another issue that needs to be address for the successful routine use of TERS.

6. Future perspectives and challenges A wide range of Raman instruments with various improvements is available today which significantly increases the area of its application especially pharmaceutical research. Highly sophisticated lab based Raman instruments with integrated assemblies are available in the market for high end research. On the other hand, more compact benchtop, portable instruments or devices with remote systems are used for on-site detection of desired components, quality control, and research.35 The technological developments in both the directions will continue to help in deeply understanding various phenomena in the area of biomedical research.

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In contrast to FTIR spectroscopy, the characterization of water containing biomaterials such as hydrogels and in situ measurements are not hindered in Raman spectroscopy due to its transparency to water. However, in case of Raman measurements of biological samples, lasers with high power might be required to get sufficient Raman scattering, which in turn can damage the cells and sample over long time. The use of Raman spectrometer in combination with the microscopes provides the possibility of analyzing the desired area of a sample. Further, on one hand, combination of SERS approach with other techniques such as magnetic resonance imaging (MRI) or photoacoustic imaging has opened new doors for in vivo diagnostic application. On the other hand, development of particles capable of showing SERS signal and controlled drug release enable us to explore new possibilities for theranostic applications in future. Coupling of remote-fiber optic probes enables the researcher to record Raman spectral details from remote locations and thus preventing the exposure to harmful materials. This technological improvement will further help in the area of process analytical technology. In recent years, there has been a tremendous demand of online manufacturing processes that have better manufacturing efficiencies with proposed quality.150 In this context, it is envisioned that Raman technique will be used at various unit operations aiming for continuous manufacturing of pharmaceuticals or other materials with strict quality control. So far, very rare attempts have been made to integrate the control sensors with a continuous tablet manufacturing process which in turn can be applied into a pilot-plant.151 It is expected that extensive closed loop operation framework will be designed exploiting the benefits of Raman method for developing advanced control strategy. Similarly, Raman spectroscopic method will gain significant interest to check the drug content uniformity in tablets, which are being manufactured in a plant, for real-time quality assurance.152 Raman method will also find applications in chemotherapy preparation units to control chemotherapy infusions adapted to each patient.153 Raman spectroscopy is of significant importance as an analytical tool in the pharmaceutical area as it provides a detailed fingerprint of the sample. Hence, its use for characterizing a new raw material and the safety, efficacy, and quality of these raw materialderived medicines will increase. One such example is Chinese herbal medicine and the use of Raman method to characterize the raw materials and adulterants, quality control of formulations, and detection of counterfeits.154 Next, highly efficient portable Raman spectrometers with new 26


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assemblies will continue to be developed in future for on-site qualitative and quantitative analysis of a variety of drugs and substances that are of forensic interest. The development of dedicated Raman imaging instrument for tumor surgeries in future is of prime importance as the clinical Raman scanners suffer with long acquisition time, low coverage area and loss of signal resolution due to compromise between spatial resolution and scanning time.155 Similarly, special attention need to be given to manufacture deep tissue Raman detectors able to detect signals through several centimeters of tissue.156 The characterization of native extracellular matrix, engineered biomaterials constructs and cell response is essential for assessing the performance of developed material for tissue engineering applications. This is generally achieved by using various approaches such as conventional biomolecule specific dyes, fluorescent antibodies, cell surface markers, flow cytometry and fluorescence microscopy. However, the disadvantages of these approaches are the higher cost and the knowledge of limited biomolecules that can be detected. In such a case, Raman spectroscopy can be used for investigating substrate composition and cell fate without using labels and also with location specificity. However, advancements in the instrumentation are necessary to make it applicable for deep layer probing. The biggest challenge for the clinical application is to develop cheaper and more efficient SERS exhibiting nanoparticles along with getting the regulatory approval for their clinical use. 60

7. Conclusions This review article provides a brief overview on the potential of Raman spectroscopy for the characterization of polymer based biomaterials which have gained a booming interest in recent years. The characterization of these biomaterials loaded with desired active molecules is essential for obtaining a deep understanding of their physicochemical behavior in order to ensure their success in clinic. Despite some limitations such as low sensitivity and fluorescence, Raman spectroscopy has emerged as a non-destructive technique for the quantitative and qualitative analysis in the area of solid dispersions, process parameters optimization, drug elution from the coatings on polymer implants, drug dissolution, microparticle composition and their intracellular distribution, tissue engineering etc. It is expected that with new technological developments in

27



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the near future Raman technique will become a popular analytical tool for pharmaceutical applications.

Acknowledgements Dr. Garima Agrawal thanks DST Inspire Faculty Award (DST/INSPIRE/04/2015/003220) of Department of Science and Technology, Government of India for the financial support. Dr. Sangram highly acknowledges the Ramanujan Fellowship (SB/S2/RJN-038/2016) of Department of Science and Technology, Government of India.

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For Table of Contents Use Only RAMAN SPECTROSCOPY FOR ADVANCED POLYMERIC BIOMATERIALS Garima Agrawala*, Sangram K. Samalb

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RAMAN SPECTROSCOPY FOR ADVANCED POLYMERIC

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