Abstract The first hyperpolarizability(£]) of five charge-transfer molecules are determined using the hyper-Rayleigh scattering (HRS) technique at two excitation wavelengths : 1064nm and 1907nm. The 1064nm excitation wavelength is derived from a Nd: YAG pulsed laser, and the 1907nm excitation wavelength is obtained by shifting the 1064nm laser light by stimulated Raman scattering of pressurized H2 gas. Four of the five samples contains thiophene and thiazole are synthetized by Prof. Shu Ching-Fong at the National Chiao Tung University (NCTU) and the other sample is synthetized by Prof. Hong, Jin-Long at the National Sun Yat-sen University (NSYSU). The measured £] values are used to calculate the intrinsic molecular hyperpolarizabilities using the two-level model previously developed by Oudar and Chemla. The results are related to molecular structure.

This dissertation reports the results of optical studies of epitaxial (e), polycrystalline (p) and amorphous (a) Ge2Sb2Te5 (GST) thin films. The dynamic properties of GST films in all three (e/p/a) phases were investigated by a time-resolved optical pump-probe technique in which a femtosecond pump pulse of 55 fs duration was used to excite the sample. The intensity and polarization of the reflected probe beam respectively provide information about the transient reflectance (R) and anisotropic reflectance (AR) induced in the sample, that in turn provide the information about the crystal structure, phonon spectrum, and ultimately phase transitions within the sample. The study of an epitaxial sample provides an opportunity to explore the character of the modes within the phonon spectrum. The epitaxial GST film was grown upon a homoepitaxial layer of GaSb grown upon a GaSb wafer. We observed a 6.7 THz coherent optical phonon (COP) in GaSb(001). The dependence of the signal strength upon the pump and probe polarization was explained in terms of a model that considered both Transient stimulated Raman Scattering (TSRS) and the action of a Surface Space-Charge (SSC) field. The presence of the 6.7 THz transverse COP in the AR channel and its four fold dependence on pump and probe polarization suggests a three-dimensional T2 character. The COP amplitude was maximum when the probe was polarized parallel to the cube edge (GaSb[100]) and the pump polarization was set parallel to a face diagonal (GaSb[110]). The results were fully understood using a microscopic model of selective bond breaking. The AR response of e-GST/GaSb(001) reveals the presence of a 3D 3.4 THz transverse optical phonon. The mode amplitude was independent of pump polarization indicating that the mode is excited by a SSC field. This SSC field could exist within the GST, if the distorted rock-salt structure of GST lacks inversion symmetry, or GaSb, which has the non-centrosymmetric zincblende structure, leading to impulsive excitation of phonons at the GST/GaSb interface. The mode in GST was inferred to be T2-like. The observation of a T2-like phonon mode confirms that GST is cubic in structure and challenges previous studies where 1D or 2D character was assigned to the 3.4 THz mode. While pump-probe measurements displayed the presence of a 3D 3.4 THz mode in the AR response of e-GST/GaSb(001), a 4.5 THz mode was observed in both R and AR channels for p-GST(37 nm)/Si(001) and a-GST(57 nm)/Si(001). The mode character was identified to be either of A or E type by comparing the frequency with frequencies reported in the literature. Additional Raman microscope measurements confirmed the presence of the modes observed in the pump-probe measurements and also revealed additional frequencies. The differences in the frequencies observed from the different samples are quite small suggesting the presence of similar bonds that are modified to some extent by the different structural environment found within each sample. After exposure to high pump fluence the original modes disappeared and were replaced by new modes with frequencies at 4.2 THz and 3.1 THz in e-GaSb, 4.2 THz in e-GST, 3.5 THz in p-GST and 3.6 THz in a-GST. The difference in the final frequencies observed for p and a-GST sample may result from the difference in stack structure affecting the time-dependent temperature profile in each sample. The dependence of the temperature profile on the sample stack was understood from an experimental study of the phase transition between the amorphous and crystalline states induced by exposure to a series of amplified laser pulses. The dependence of the crystalline area and its reflectivity upon the number of pulses and fluence was described using a simple algebraic model. The results justify the assumption of one-dimensional heat flow. The growth velocity of the crystalline region was calculated to be 7-9 m/s. Apparatus and methods were developed to extend the time-resolved optical studies described previously. Firstly, an apparatus was constructed for the measurement of the wavelength dependent sample reflectance with a white-light pulse. A reference arm was employed to allow normalization and hence removal of the intensity noise arising in the laser regenerative amplifier system. Secondly an electrical measurement apparatus was constructed to allow combined electro-optical measurements in future. Switching of GST vertical memory cells was successfully demonstrated. The cells were fabricated on a borosilicate substrate with TiW top and bottom electrodes. A DC voltage of 4.5 to 6 V was required to induce switching, while in pulsed measurements, the device demonstrated switching in response to a pulse with minimum duration of 100 ns.

We study the behavior of electric fields in and around dielectric and metal nanoparticles, and prepare the ground for their applications to a variety of systems viz. photovoltaics, imaging and detection techniques, and molecular spectroscopy. We exploit the property of nanoparticles being able to focus the radiation field into small regions and study some of the interesting nonlinear, and quantum coherence and interference phenomena near them. The traditional approach to study the nonlinear light-matter interactions involves the use of the slowly varying amplitude approximation (SVAA) as it simplifies the theoretical analysis. However, SVVA cannot be used for systems which are of the order of the wavelength of the light. We use the exact solutions of the Maxwell's equations to obtain the fields created due to metal and dielectric nanoparticles, and study nonlinear and quantum optical phenomena near these nanoparticles. We begin with the theoretical description of the electromagnetic fields created due to the nonlinear wavemixing process, namely, second-order nonlinearity in an nonlinear sphere. The phase-matching condition has been revisited in such particles and we found that it is not satisfied in the sphere. We have suggested a way to obtain optimal conditions for any type and size of material medium. We have also studied the modifications of the electromagnetic fields in a collection of nanoparticles due to strong near field nonlinear interactions using the generalized Mie theory for the case of many particles applicable in photovoltaics (PV). We also consider quantum coherence phenomena such as modification of dark states, stimulated Raman adiabatic passage (STIRAP), optical pumping in $4$-level atoms near nanoparticles by using rotating wave approximation to describe the Hamiltonian of the atomic system. We also considered the behavior of atomic and the averaged atomic polarization in $7$-level atoms near nanoparticles. This could be used as a prototype to study any $n-$level atomic system experimentally in the presence of ensembles of quantum emitters. In the last chapter, we suggested a variant of a pulse-shaping technique applicable in stimulated Raman spectroscopy (SRS) for detection of atoms and molecules in multiscattering media. We used discrete-dipole approximation to obtain the fields created by the nanoparticles.

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Η χρήση των πολυμερών στον τομέα της ιατρικής βιομηχανίας κερδίζει ολοένα και μεγαλύτερο έδαφος τα τελευταία χρόνια έχοντας ήδη κάνει ισχυρή την παρουσία τους σε ένα ευρύ πεδίο κλάδων της βιοϊατρικής όπως στη μηχανική ιστών, στην εμφύτευση ιατρικών συσκευών και τεχνητών οργάνων, στην προσθετική και την οφθαλμολογία, στην οδοντιατρική και την αποκατάσταση οστών, στη χημειοθεραπεία και σε ποικιλία άλλων ιατρικών εφαρμογών. Με τη χρήση πολυμερικών συστημάτων μεταφοράς δραστικών ουσιών καθίσταται ικανή η ελεγχόμενη αργή αποδέσμευση φαρμάκων στο σώμα καθώς και η στοχευμένη απελευθέρωσή τους σε σημεία όπου υπάρχουν φλεγμονές ή όγκοι. Τοιουτοτρόπως, χημειοθεραπείες με χρήση βιοπολυμερών ως διαμεσολαβητές, προβάλλουν ως δυνητικές υποψήφιοι στην αντιμετώπιση του καρκίνου του εγκεφάλου με ενθαρρυντικά αποτελέσματα. Συγκρινόμενη με την τυπική συστημική χημειοθεραπεία, η ενδοογκική απελευθέρωση φαρμάκου με τη χρήση βιοπολυμερών θεωρητικώς παρουσιάζει αρκετά πλεονεκτήματα: τα βιοπολυμερή μπορούν να μεταφέρουν το φάρμακο απευθείας στον όγκο-στόχο αυξάνοντας τη συγκέντρωση τοπικά και παράλληλα μειώνοντας τη συστημική τοξικότητα· μπορούν έτσι να χρησιμοποιούνται στη θεραπεία ανοσοκατασταλμένων ασθενών που δεν μπορούν να υποβληθούν σε συστημική χημειοθεραπεία. Από τη στιγμή που είναι απαραίτητη η ποσοτικοποίηση των φαρμάκων για τον χαρακτηρισμό των συστημάτων αποδέσμευσης και για μελέτες φαρμακοκινητικής, θα πρέπει να επιλέγεται η καταλληλότερη μέθοδος ποσοτικοποίησης παρέχοντας υψηλή ευαισθησία και ακρίβεια, εξασφαλίζοντας μεγάλη ανιχνευτική ικανότητα ακόμη και για πολύ χαμηλές συγκεντρώσεις. Στην παρούσα εργασία δύο αναλυτικές τεχνικές, η απορρόφηση υπεριώδους-ορατού και η επιφανειακή ενίσχυση της σκέδασης Raman (Surface Enhanced Raman Scattering, SERS), χρησιμοποιήθηκαν για την ποσοτική εκτίμηση του αντινεοπλασματικού φαρμάκου Mitoxantrone και του αντιμυκητιακού παράγοντα Ambisome (Αμφοτερισίνη Β) που αποδεσμεύτηκαν από βιοσυμβατές πολυμερικές μήτρες συμπολυμερούς αιθυλενίου-οξικού βινυλεστέρα, συμπολυμερούς γλυκολικού-γαλακτικού οξέος και πολυπροπυλενίου. Το SERS είναι ένα νέο, εναλλακτικό, ταχύ και μη καταστροφικό εργαλείο που μπορεί να βρεί εφαρμογή και στην ποσοτική εκτίμηση ουσιών πάρα πολύ χαμηλών συγκεντρώσεων. Χάρις στην ενίσχυση που παρέχεται στο σήμα Raman από τα νανο-εκτραχυμένα υποστρώματα ευγενών μετάλλων ή τα νανο-συσσωματώματα κολλοειδών διαλυμάτων ευγενών μετάλλων, έχει αναφερθεί ακόμη και συλλογή φάσματος SERS από ένα μόνο μόριο. Συνεπώς, η εφαρμογή του SERS σε μελέτες ουσιών εξαιρετικά χαμηλών συγκεντρώσεων φαίνεται να είναι πολύ ενδιαφέρουσα. Κατασκευάστηκαν πολυμερικά υμένια με εγκλωβισμένες τις δραστικές ουσίες και η μελέτη αποδέσμευσης πραγματοποιήθηκε σε νερό. Ποσοτικές μετρήσεις με τη χρήση του SERS σε πολύ μικρές συγκεντρώσεις έδειξαν μεγαλύτερη ανιχνευτική ευαισθησία σε σχέση με αυτές που πραγματοποιήθηκαν με την απορρόφηση UV-Vis. Συμπερασματικά, το SERS δείχνει ικανό στον ποσοτικό προσδιορισμό ενεργών ουσιών που αποδεσμεύονται από βιοσυμβατά πολυμερικά συστήματα μεταφοράς δραστικών ουσιών σε πολύ μικρές συγκεντρώσεις. / The application of polymeric materials for medical purposes is growing very fast. Polymers have found applications in such diverse biomedical fields as tissue engineering, implantation of medical devices and artificial organs, prosthesis, ophthalmology, dentistry, bone repair, chemotherapy and many other medical fields. Polymer-based delivery systems enable controlled slow release of drugs into the body and also they make possible targeting of drugs into sites of inflammation or tumors. Thus, biopolymer-mediated chemotherapy has shown promising results in the treatment of brain tumors. When compared to conventional systemic chemotherapy, intratumoral biopolymer-mediated drug delivery has several theoretical advantages: Biopolymers can deliver drugs into the tumor bed, thus maximizing local concentration while minimizing systemic toxicity. They may therefore be employed in the treatment of immunodepressed patients etc. Since drugs need to be quantified for drug delivery system characterization, intracellular distribution studies, free or vehicular, and for pharmacokinetic assays, the most suitable quantification method must be chosen. It should have a high sensitivity, specificity and reproducibility and should be capable of measuring at very low concentration range, as well. In the present study, two analytical techniques are utilized to quantitatively evaluate the antineoplastic drug Mitoxantrone and the antifungal agent Ambisome (Amphotericin b) released from active agents-loaded biocompatible polymer matrices poly(propylene), poly(ethylene-co-vinyl acetate), poly(lactic-co-glycolic acid); the UV-Vis absorption and the Surface Enhance Raman Scattering (SERS). SERS is a new, versatile, fast and non destructive tool for the estimation of extremely small amounts of substances. Due to the enhancement provided to the Raman signal by the nano-rough noble-metal substrates or the nano-structured colloidal clusters of noble metals, even single molecule detection has been reported. Therefore, applying SERS to extremely low concentration measurements proves to be challenging. Drug loaded polymer specimens were prepared and the in vitro drug release was determined in water. Fast SERS quantitative measurements showed enhanced sensitivity compared to the UV-Vis absorption; SERS may enable low concentration quantitative assessment of controlled release of drugs from biopolymer-based delivery systems.

La peau est un organe qui enveloppe le corps, elle est une barrière naturelle importante et efficace contre différents envahisseurs. Pour le traitement des maladies dermatologiques ainsi que dans l'industrie cosmétique, les applications topiques sur la peau sont largement utilisées. Ainsi beaucoup d'efforts ont été investis dans la recherche sur la peau visant à comprendre l'absorption moléculaire et les mécanismes rendant efficace la pénétration. Cependant, il reste difficile d'obtenir une visualisation 3D de haute résolution combinée à une information chimique- ment spécifique et quantitative dans la recherche sur la peau. La spectroscopie et la microscopie non-linéaire, incluant la fluorescence excitée à 2-photon (TPEF), la diffusion Raman spontanée, la diffusion Raman cohérente anti-Stokes (CARS) et la diffusion Raman stimulée (SRS), sont introduits dans ce travail pour l'identification sans ambiguïté de la morphologique de la peau et la détection de molécules appliquées de façon topique. Plusieurs méthodes quantitatives basées sur la spectroscopie et la microscopie non-linéaire sont proposées pour l'analyse chimique en3D sur la peau artificielle, ex vivo et in vivo sur la peau humaine. De plus, afin de s'adapter aux applications cliniques à venir, un design endoscopique est étudié pour permettre l'imagerie non-linéaires dans les endoscopes flexibles. / Skin is an organ that envelops the entire body, acts as a pivotal, efficient natural barrier to- wards various invaders. For the treatment of major dermatological diseases and in the cosmetic industry, topical applications on skin are widely used, thus many efforts in skin research have been aimed at understanding detailed molecular absorption and efficient penetration mechanisms. However, it remains difficult to obtain high-resolution visualization in 3D together with chemical selectivity and quantification in skin research. Nonlinear spectroscopy and microscopy, including two-photon excited fluorescence (TPEF), spontaneous Raman scattering, coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS), are introduced in this work for unambiguous skin morphological identification and topical applied molecules detection. Sev- eral quantitative methods based on nonlinear spectroscopy and microscopy are designed for 3D chemical analysis in reconstructed skin, ex vivo and in vivo on human skin. Furthermore, to adapt to forthcoming clinical applications, an endoscopic design is investigated to bring nonlin- ear imaging in flexible endoscopes.

Nonlinear optical microscopy is a collection of very powerful imaging techniques. Linear optical microscopes probe the refractive index and absorption, which both stem from the first-order linear electric susceptibility. Especially in biological tissue, the variation in the refractive index is often small and the tissue is, in many cases, transparant. Nonlinear optical microscopes on the other hand probe the nonlinear higher-order susceptibilities, which can be chemically sensitive, leading to the capability to achieve label-free imaging. Nonlinear optical microscopes have been in development for more than thirty years and they are based on numerous nonlinear optical processes. The ones I will concentrate on in this thesis are second harmonic generation (SHG), coherent anti-Stokes Raman scattering (CARS), and stimulated Raman Scattering (SRS). The first technique is commonly used to image collagen as those molecules have a particularly large second-order nonlinear susceptibility due to their chiral structure. CARS and SRS on the other hand are often used because they resonantly target vibrational resonances in molecules, giving rise to the aforementioned label-free imaging. Deep understanding of the nonlinear imaging process is crucial to the interpretation of the images these techniques produce. Computational tools are exceptionally suited for this task as they allow studying the electromagnetic field anywhere in the sample as well as the far-field, and one can change any of the material properties to study their effect. One such tool is finite-difference time-domain (FDTD) that our group developed for nonlinear optical microscopy simulations. It is a direct discretization of Maxwell's equation. While computationally costly, it does allow any arbitrary shaped sample to be simulated. The sample can have frequency dependent refractive indexes, and also nonlinear media with third-order nonlinearities such as Kerr media and Raman-active media, but also second-order nonlinearities for SHG. The code is designed in such a way that it can run on thousands of CPUs on a wide variety of compute cluster which allows our group to obtain nanoscale resolution. Another computational tool I use is the free-space Green's function solution to the Helmholtz equation, which can be used to calculate the Hertz vector in the frequency domain, both in the near- and far-field, based on the induced nonlinear polarization. The electric field is then calculated from this Hertz vector. This technique is much faster then FDTD and also allows for arbitrary shapes of the nonlinear electric susceptibility in the sample. However, it assumes a homogeneous refractive index throughout the entire spatial domain and requires complete knowledge of the input beam or beams that induce the nonlinear polarization. In this thesis, I use these tools to study the image formation process of various nonlinear optical processes mentioned earlier. For example, I study the effect of an inhomogeneous refractive index on the images produced by these microscopes. In literature the index of refraction is almost always assumed to be homogeneous, because, as mentioned before, the inhomogeneity of the refractive index is often small. However, I show that these small differences in the index of refraction can have a significant effect on the measured far-field intensity signal. For example, in SRS and CARS images, the measured signal can increase by an order of magnitude depending on the index mismatch and structure of the sample. Additionally, significant shifts in perceived position occur. Even nonresonant nonlinear signals can be evoked purely through a mismatch in linear refractive index. Computational modelling can also help reveal additional detail. As SHG is a coherent process, subwavelength information can be inferred through the phase information. Our experimental collaborators built an interferometric SHG (I-SHG) microscope for exactly that purpose. We used this to image collagen fibrils, which are all aligned in a parallel fashion. However, because collagen fibrils have a chiral molecular structure, they can point either ``up'' or ``down''. Using my Green's function simulations of the SHG imaging process of collagen fibrils, I was able to predict the standard deviation in the measured phase and link it to the orientation of collagen fibrils in the focal spot of the probing laser beam, even though the diameters are far below the minimum resolvable capabilities of the microscope. We found that the ``upwards'' fibrils make up 46--53% of the sample. Even with a normal SHG microscope that does not measures phase, additional subresolution information is obtainable. With our collaborators we measured the ratio of the forward SHG intensity signal to that in the backward direction and with my simulations, we are able to link this to the fibril diameters in collagen tissue. Thus we inferred that the fibril diameter increases as a function of tissue depth. Furthermore, a computational technique called ptychography is able to retrieve phase information without an interferometric reference beam. Additionally, it increases resolution to the theoretical limit, independent of the laser focal spot size, and corrects for distortions in the input beam as well. I have developed this technique for use with nonlinear optical microscopy and was able to show it is a viable alternative to I-SHG by imaging simulated rat tail tendon at the diffraction limit while retrieving the orientation of the fibrils through the phase of the SHG signal. I also implemented the algorithm for CARS, where the phase information can be used to greatly increase the signal-to-noise ratio by reducing the nonresonant background radiation that results from competing nonlinear optical processes. I showed an example of this by imaging a simulated fibroblast cell where the CARS process was tuned to the lipid droplets inside of the cell. I am currently in talk with experimentalists to apply this theoretical technique to experiments as that would further demonstrate the impact of my work. Finally, keeping in theme with the collagen fibrils, I show that the ratio of the forward SHG signal to the backward signal, the F/B ratio, is affected by a mismatch in the refractive index for fibrils larger than 100nm. This measure is an indicator of fibril diameter and thus important for making qualitative predictions. Single fibrils are generally too small to be significantly affected by near-field effects, but the bigger fibrils can be. Fibrils in rat tail tendon have a distribution of fibrils diameters and the large fibrils occur infrequent. However, I found that the large fibrils are largely responsible for the forward as well as backward signal, thus refractive index mismatches still affect the F/B ratio significantly despite their infrequency. The F/B ratio for a collection of fibrils placed in a n=1.47 medium was found to be 31.8±0.7% higher than for those in a n=1.33 medium. Our experimental colleagues have done preliminary measurements on mouse tail tendon where they found an increase of 40±20%, in line with the value of 28.1±0.6% that I found for simulations with mouse tail tendon. In conclusion, the theoretical tools I have used in my thesis have provided me with the ability to study nonlinear optical image formation processes with a level of detail that would be near-impossible to do experimentally. I have used this ability to show how refractive index mismatches, such as those found in biological tissue, can significantly distort the far-field intensity signals. I have shown this for SRS and CARS where the far-field intensity signal appeared an order-of-magnitude larger compared to the same sample without a refractive index mismatch with the background medium. Additionally, shifts in the perceived position of the object under investigation were observed and I showed the presence of a nonresonant background signal in AM-SRS. Likewise I showed that in the SHG imaging of collagen fibrils significant changes in the F/B ratio can occur. All of these effects have important implications as these types of images as biomedical researches rely on the correct interpretation of nonlinear optical microscopy images for both research and diagnostics. Apart from showing the effect of a refractive index mismatch, I have also shown that computation modelling can be used to infer subwavelength features in SHG imaging experiments of collagen fibril such as fibril orientation and fibril diameter. These methods have the potential to aid medical researchers as changes in the structure of collagen are often an early indicator of diseases such as osteoarthritis. Finally, I showed that the ptychography algorithm I developed for nonlinear optical microscopy is able to retrieve phase information of the nonlinear electric susceptibility in SHG and CARS imaging while also enhancing the resolution and correcting for distortions in the input beams. I can also use much larger laser spot sizes than in conventional experiments without compromising the obtained resolution, thus fewer measurements are required. The technique is not limited to SHG and CARS either; it will work for other nonlinear optical processes as well. Experimental verification of nonlinear ptychography will be done soon. This technique has to potential to significantly improve current imaging techniques since access to the phase information allows one to observe additional information about the sample as we showed with the I-SHG microscope.

In der vorliegenden Dissertation werden verschiedene plasmonisch aktive Kern/Schale- Nanopartikel synthetisiert, experimentell und theoretisch charakterisiert und in analytischen Anwendungen der oberflächenverstärkten Raman-Spektroskopie (engl. surface-enhanced Raman scattering, SERS) eingesetzt. Es werden die optischen Eigenschaften von Gold/Silber-Nanoschalen mit durchstimmbaren Plasmonbanden behandelt. Motivation dafür ist die Frage nach optimalen SERS-Markern für die rote Laseranregung (λ = 632.8 nm). In SERS-Anwendungen gibt es die Möglichkeit mehrere Marker-Moleküle auf die Oberfläche der Nanopartikel aufzubringen, um so eine erhöhte Multiplexing-Kapazität zu generieren. Diese Option der gemischten Monolagen wird in der vorliegenden Arbeit untersucht. Es werden SERS-Marker-Konzepte für die rote Laseranregung basierend auf einzelnen Nanopartikeln gezeigt. Außerdem wird dargestellt, inwieweit sich durch die Anordnung von Nanopartikeln in allen drei Raumdimensionen neue SERS-Marker- Konzepte mit sehr guten plasmonischen Eigenschaften realisieren lassen. In den oben beschriebenen Kapiteln übernehmen Nanopartikel die Rolle des SERS-Substrats für den selektiven Nachweis eines bestimmten Zielmoleküls (z.B. Antigens). Neben diesen Anwendungen können Nanopartikel jedoch auch noch als SERS-Substrat für die markierungsfreie Detektion von Analytmolekülen eingesetzt werden. In dieser Dissertation wird die Herstellung, Charakterisierung und der Einsatz eines integrierten SERS-Substrats für die kombinierte Festphasensynthese und Analytik mittels plamonisch aktiver Gold/Glas-Kern/Schale-Nanopartikel auf Harz-Mikrokugeln behandelt.