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Das Ziel dieser randomisierten, klinischen 12-Monatsstudie war die Untersuchung der Performance des Universaladhäsivs iBond® Universal an Restaurationen von nicht-kariöse Zahnhalsläsionen (NCCL) sowohl klinisch mittels FDI Kriterien als auch mittels Analyse des Zahn-Komposit-Verbundversagens mittels optischer Kohärenztomografie (OCT). An 50 Patienten wurden je drei bzw. vier NCCLs mit dem Universaladhäsiv iBond Universal (iBU, Kulzer) in den Konditionierungsmodi self-etch (iBU-SE, n = 50), selective-enamel-etch (iBU-SEE, n = 29) und etch-and-rinse (iBU-ER, n = 50) und mittels des Komposit Venus® Diamond Flow restauriert. Als Referenzadhäsiv (Kontrollgruppe) diente das Etch-and-rinse-Adhäsiv OptiBond™ FL (OFL, Kerr, n = 50). Die quantitative Bewertung der interfazialen Spaltformation an Schmelz und Dentin/Zement mittels OCT begann bereits initial (direkt nach Füllungslegung), nach 14 Tagen, nach sechs und zwölf Monaten, während die klinische Bewertung mittels FDI-Kriterien erst nach 14 Tagen begann und dann parallel zur tomografischen Untersuchung erfolgte. Es wurden die kumulativen Fehlerraten (für Randverfärbung, Randadaptation, Frakturen/Retention) berechnet und Kaplan-Meier-Kurven erstellt sowie die gemittelten adhäsiven Defekte pro Gruppe statistisch ausgewertet. Nach zwölf Monaten waren die kumulativen Fehlerraten mit iBU in allen Applikationsmodi signifikant (iBU-SE, iBU-SEE, Fehlerraten je 0,0%) bzw. nicht signifikant (iBU-ER, Fehlerrate 2,1%) geringer als mit OFL. Es ergaben sich für die Randadaptation und Randverfärbung keine signifikanten Gruppenunterschiede, lediglich bei der Gruppe OFL wurden tendentiell beim Kriterium Randadaptation mehr Restaurationen mit Score 2 bewertet als in der Gruppe iBU-SE. Die interfazialen Spalte nahmen innerhalb von 12 Monaten in allen Gruppen signifikant zu. Am Schmelz wurden für iBU-SE von initial bis zwölf Monate signifikant mehr adhäsive Defekte als in der Gruppe OFL und von t1 bis t3 signifikant mehr im Vergleich zu iBU-ER sowie ab t2 bis t3 mehr gegenüber iBU-SEE festgestellt. Am Dentin/Zement wurden mit iBU in allen Modi signifikant weniger adhäsive Defekte als mit OFL sowie ab t2 bis t3 weniger im Modus SE gegenüber ER festgestellt. Das mit dem Referenzadhäsiv OFL im Vergleich zu iBU signifikant häufigere Verbundversagen an der Dentin/Zement-Komposit-Interface (OCT) korrespondiert mit dem nach 12 Monaten signifikant erhöhten Auftreten von Füllungsverlusten in dieser Gruppe. Mit OCT waren die Gruppenunterschiede bereits initial (iBU-SEE, Dentin) bzw. nach 14 Tagen (alle Modi, Dentin und Dentin/Zement) statistisch verifizierbar. Die klinische Bewertung der Restauration lässt diese Aussage erst nach 12 Monaten für die Gruppen iBU-SE und iBU-ER (Trend) zu. Das gesteigerte Verbundversagen an der Dentin-Komposit- bzw. Dentin/Zement-Komposit-Interface in der Gruppe iBU-ER im Vergleich zur Gruppe iBU-SE hat sich hingegen klinisch nach 12 Monaten noch nicht durch eine geringere Retentionsrate in Gruppe iBU-ER manifestiert. Anhand der geringeren Streuung der Messwerte lässt sich vermuten, dass das Universaladhäsiv iBond Universal insbesondere im Modus SEE gegenüber OFL weniger techniksensitiv ist. Die optische Kohärenztomographie ermöglicht das Monitoring von Restaurationen, insbesondere die Progression des interfazialen Zahn-Komposit-Verbundversagens. Die Bewertung des Zahn-Komposit-Verbundversagens könnte geeignet sein, um die klinische Bewährung eines Adhäsivs frühzeitig zu beurteilen.:1. Einführung in die Thematik 1.1 Adhäsivsysteme 1.2 Methoden zur Bewertung des adhäsiven Verbundes in vivo 1.3 Optische Kohärenztomografie 2. Zielsetzungen und Hypothesen 3. Publikationsmanuskript 4. Zusammenfassung 5. Literaturverzeichnis 6. Darstellung des eigenen Beitrags 7. Selbstständigkeitserklärung 8. Wissenschaftliche Veröffentlichung 9. Lebenslauf 34 10. Danksagung 35

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23828号 / 人健博第99号 / 新制||人健||7(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 椎名 毅, 教授 杉本 直三, 教授 辻川 明孝 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

This thesis intends to familiarize the reader with the concepts of photon statistics and correlations in quantum optics. Developing light sources that emit quantum states is central for the realization of quantum technologies. One important step in characterizing these sources is the measurement of field fluctuations and correlations, by coincidence measurements. The expectation value of a coincidence measurement, a simultaneous measurement of two intensities (or, more general, four fields), is represented by the fourth-order correlation function. The value of the correlation function, at zero delay between the detection of two photons, reveals important properties of the state to which they belonged, for example the fluctuations of the photon number. Since predictability is important for many applications, light sources emitting single photons are also characterized by the indistinguishability of consecutively emitted photons, or of two photons from separate emitters. In paper I we investigate blinking behaviour in quantum emitters, and its effect on the interference pattern and photon statistics with photons from two separate emitters. Blinking refers to an emitters transition into a non-emitting state, and subsequent transition back to an emitting state. We show that blinking can not be treated as linear loss, when measuring the fourth-order correlation function for two emitters in a Hong-Ou-Mandel setup. In general, a measurement of the fourth-order correlation function is robust to loss, which makes it a very practical tool. However, the relation between recorded coincidence counts and the correlation function is only direct in the limit of zero detection efficiency, and depends on the detection system. In paper II, we show that by adding a variable attenuation in the beam path, we can trace back to the ''true'' value of the correlation function at zero quantum efficiency. This method improves accuracy in correlation measurements by decreasing a systematic error at the expense of an increased statistical error, which is easier to handle, extending the use of coincidence methods to classical and non-classical multi-photon states. / <p>QC 20180517</p>

The heart, as a vital organ, must pump continuously to deliver oxygenated blood to the tissues of the body. The physical stress of pumping is supported by the extracellular matrix (ECM), a dynamic protein scaffold inside and around the heart. While a regulated ECM is required to maintain heart function, aberrant or excessive ECM remodelling, called fibrosis, is associated with disease states and is a hallmark of cardiovascular disease. One major trigger of cardiovascular disease is obesity, and fibrotic remodelling is known to occur in this context. In order to study the impact of increased body size on heart function and the molecular and biophysical characteristics of the ECM, a larval overgrowth model for obesity in the genetic model Drosophila melanogaster has been developed and characterised. This model produces giant larvae twice as heavy as their wildtype counterparts, and allows a unique opportunity to study changes in the cardiac ECM in a simple genetic model. Results demonstrate a remarkable ability of the ECM to accommodate this increase in size. The muscles of the heart are particularly robust, and there are no obvious observable defects to the matrix. Preliminary results suggest Collagen fibres are thicker and more disperse. When observing heart functionality, the cross-sectional area of the heart lumen is increased significantly in giant larvae, both at diastole and systole. However, giant larvae display defects in contraction of the heart tube, characterised by an inability to contract fully at systole. This results in a less than proportional increase in stroke volume, and an increase in heart rate. Heart function of giant larvae is clearly affected by the increase in body size. To quantify the impact to the biophysical structure of the ECM, an atomic force microscopy protocol is being developed. / Thesis / Master of Science (MSc) / A known side effect of cardiovascular disease is fibrosis of the heart, a form of pathological extracellular matrix (ECM) remodelling. Fibrosis causes the stiffening of heart muscle, leading to impaired cardiac function. One of the main risk factors for the development of cardiovascular disease is obesity, and fibrosis is known to occur in this context. I have characterised changes in the morphology and physiology of the heart in a Drosophila model for obesity. The resulting cardiac hypertrophy reveals significant plasticity in the heart ECM, while heart contraction and output is compromised.

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The uterosacral ligaments (USLs) are important anatomical structures that support the uterus and apical vagina within the pelvis. As these structures are over-stretched, become weak, and exhibit laxity, pelvic floor disorders such as pelvic organ prolapse occur. Although several surgical procedures to treat pelvic floor disorders are directed toward the USLs, there is still a lot that is unknown about their function. These surgeries often result in poor outcomes, demonstrating the need for new surgical approaches and biomaterials. The first chapter of this dissertation presents a review of the current knowledge on the mechanical properties of the USLs. The anatomy, microstructure, and clinical significance of the USLs are first reviewed. Then, the results of published experimental studies on the {emph{in vivo}} and {emph{ex vivo}}, uniaxial and biaxial tensile tests are compiled. Based on the existing findings, research gaps are identified and future research directions are discussed. The second chapter proposes the use of planar biaxial testing, digital image correlation (DIC), and optical coherence tomography (OCT) to quantify the deformations of the USLs, both in-plane and out-of-plane. Using virgin swine as an animal model, the USLs were found to deform significantly less in their main direction (MD) of {emph{in vivo}} loading than in the direction perpendicular to it (PD) at increasing equibiaxial stresses. Under constant equibiaxial loading, the USLs deformed over time equally, at comparable rates in both the MD and PD. The thickness of the USLs decreased as the equibiaxial loading increased but, under constant equibiaxial loading, the thickness increased in some specimens and decreased in others. The third chapter presents new experimental methods for testing the {emph{ex vivo}} tensile properties of the uterosacral ligaments (USLs) in rats. USL specimens were carefully dissected to preserve their anatomical attachments, and they were loaded along their main {emph{in vivo}} loading direction (MD) using a custom-built uniaxial tensile testing device. This chapter reports the first mechanical data on the rat USLs in isolation from surrounding organs. It is also the first experimental study to provide measurements of the inhomogeneous deformations of the USLs during loading along their main textit{in vivo} loading direction, revealing that the USLs may behave as auxetic structures. The fourth and final chapter presents preliminary findings on novel imaging applications to characterize the evolving structure of the USLs before, during, and after tensile pulling along the ligaments' main textit{in vivo} axis of loading. Rat USLs were excised using the proposed novel dissection method and pulled uniaxially as was performed in the previous chapter. Before and after mechanical testing, second harmonic generation (SHG) was used to image collagen and muscle within the three anatomical regions of the USLs. During mechanical testing, OCT was used to collect out-of-plane images of the cervical/intermediate regions of the USL specimens, resulting in 3D volume scans of the regions. SHG images showed the USLs to have complex microstructures with significant wavy collagen bundles interwoven with muscle bundles. Preliminary observation of the microstructure during testing revealed interwoven sections of tissue with collagenous fibers that reoriented in all directions illustrating how the USLs may expand laterally during uniaxial loading, causing the auxetic properties documented in the previous chapter. Though more quantitative work remains to be done, the findings presented in this dissertation improve our understanding of how the USLs deform with increasing load, such as what occurs during pregnancy. Together, these studies serve as a springboard for future investigations on the supportive function of the USLs in animal models by offering guidelines on testing methods that capture their complex mechanical behavior. / Doctor of Philosophy / The uterosacral ligaments (USLs) are important anatomical structures that support the uterus and vagina and are often used to restore the support of pelvic organs during surgeries for pelvic organ prolapse. These surgeries often result in poor outcomes, demonstrating the need for new surgical approaches and graft materials. Due to their supportive role, the mechanical properties of the USLs are important for their physiological function, and they must be investigated to improve current treatment strategies for pelvic organ prolapse. To this end, we designed new equipment, dissection, and testing methods to characterize the mechanical behavior of the USLs using swine and rats as animal models. We provided the first three-dimensional characterization of time-dependent deformations of swine USLs as they were pulled along their two physiological loading directions using advanced imaging methods, including digital image correlation and optical coherence tomography. We isolated the USLs from rats with their anatomical attachments and mechanically tested them along their main physiological loading direction, reporting the first mechanical data on the rat USLs in isolation from surrounding organs. Finally, we used the advanced imaging techniques optical second harmonic generation microscopy and optical coherence tomography to determine how the microstructure (e.g., collagen and muscle) of the rat USLs evolves before, during, and after mechanical testing. These findings advance our understanding of the three-dimensional, nonlinear, heterogeneous, elastic, and viscoelastic deformations of the USLs. Our work may serve as a springboard for future investigations on the supportive function of the USLs by offering guidelines on testing methods that capture their complex mechanical behavior.

The emergence of microneedle (MN) technologies offers a route for a pain free, straightforward and efficient way of transdermal drug delivery, but technological barriers still exist which pose significant challenges for manufacture of MN systems with high volume outputs at low cost. The main aim of this research was to develop new ways for MN manufacture primarily using micro-injection moulding processes with high performance engineering thermoplastics. During the moulding process these polymeric melts will be subjected to extreme stress and temperature gradients and detailed material characterisation combined with in-line monitoring is desirable to optimise the moulding parameters and will help in achieving sharp microneedles with acceptable quality. Hence high shear rheology of these selected materials was performed at wall shear rates carried out in excess of 107 s-1 over a range of temperatures to predict the flow behaviour of polymer melts at such high shear strain rates. This information was fed into injection moulding simulation software tools (Moldflow) to assist the MN production process design. The optimal design was then used to produce a full 3D solid model of the injection mould and mould insert. Furthermore various design of experiments were conducted considering input parameters such as injection pressure, injection speed, melt temperature, filling time and mould cavity temperature. Response variables including product quality and data acquired from the cavity pressure and temperature transducers were used to optimise the manufacturing process. The moulded MNs were geometrically assessed using a range of characterisation techniques such as atomic force microscopy, confocal microscopy and scanning electron microscopy. An attempt to make hollow MNs was performed and encountered many challenges like partial cavity filling and part ejection during processing. Studies were carried out to understand the problem and identified the major problem was in tool design and improvements to the moulding tool design were recommended. Plasma treatment and mechanical abrasion were employed to increase the surface energy of the moulded polymer surfaces with the aim of enhancing protein adsorption. Sample surface structures before and after treatment were studied using AFM and surface energies have been obtained using contact angle measurement and calculated using Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness resulting in better adsorption and release of BSA. To assist design-optimisation and to assess performance, a greater understanding of MN penetration behaviour is required. Contact stiffness, failure strength and creep behaviour were measured during compression tests of MN against a steel surface, and in-vitro penetration of MNs into porcine skin. The MN penetration process into porcine skin was imaged using optical coherence tomography. Finally, a finite element model of skin was established to understand the effect of tip geometry on penetration. The output of findings from this research will provide proof of concept level development and understanding of mechanisms of MN penetration and failure, facilitating design improvements for micro-injection moulded polymeric MNs.

Laser-based photo-thermal therapies can provide minimally-invasive treatment of cancers. Their effectiveness is limited by light penetration depth in tissue due to its highly scattering properties. The highly disordered refractive index distribution in tissue leads to multiple-scattering of incident light. It has been hypothesized that mechanical compression has a great potential to enhance the capabilities of laser therapy by inducing localized water transport, decreasing the refractive index mismatch, and decreasing the scattering coefficient of tissue. To better understand this process, we investigated the refractive index change of ex-vivo dog skin during mechanical compression using a swept-source optical coherence tomography (OCT) device built in our lab. The Lorentz-Lorenz rule of mixtures was applied to evaluate the water and protein weight fraction of tissue simultaneously. Results show that the refractive index of skin increased from 1.38 to 1.52 during compression and water content decreased about 60%-70% when the skin sample was compressed by 70%. In addition, we conducted compression experiments on human finger, palm, back of hand, and front of forearm in vivo. OCT images of these skin sites before and after compression by 1 minute were compared. Optical thickness of epidermis and light penetration depth in the dermis were measured. The extended Huygens-Fresnel model was applied to measure the scattering coefficient μs of skin specimens. μs of skin was measured to be about 10-17 mm-1 before compression and decreased 60%-80% after compression, which increases the averaged light intensity by 2-7 dB and almost doubles light penetration depth in dermis. It is quite significant in laser therapies especially for treating epithelia cancers which originate at 1-2 mm beneath the tissue surface. In the OCT imaging of skin dehydration experiment, we conclude that dehydration is an important mechanism of mechanical clearing. / Master of Science

Yes / Recent developments in optical coherence tomography (OCT) technology enable direct enface visualisation of retinal nerve fibre bundle (RNFB) loss in glaucoma. However, the optimum depth at which to visualise RNFBs across the retina is unknown. We aimed to evaluate the range of depths and optimum depth at which RNFBs can be visualised across the retina in healthy eyes. The central ± 25° retina of 10 healthy eyes from 10 people aged 57–75 years (median 68.5 years) were imaged with spectral domain OCT. Slab images of maximum axial resolution (4 μm) containing depth‐resolved attenuation coefficients were extracted from 0 to 193.5 μm below the inner limiting membrane (ILM). Bundle visibility within 10 regions of a superimposed grid was assessed subjectively by trained optometrists (n = 8), according to written instructions. Anterior and posterior limits of RNFB visibility and depth of best visibility were identified for each grid sector. Effects of retinal location and individual eye on RNFB visibility were explored using linear mixed modelling with likelihood ratio tests. Intraclass correlation coefficient (ICC) was used to measure overall agreement and repeatability of grading. Spearman’s correlation was used to measure correlation between depth range of visible RNFBs and retinal nerve fibre layer thickness (RNFLT). Retinal location and individual eye affected anterior limit of visibility (χ2(9) = 58.6 and 60.5, both p < 0.0001), but none of the differences exceeded instrument resolution, making anterior limit consistent across the retina and different eyes. Greater differences were observed in the posterior limit of visibility across retinal areas (χ2(9) = 1671.1, p < 0.0001) and different eyes (χ2(9) = 88.7, p < 0.0001). Optimal depth for visualisation of RNFBs was around 20 µm below the ILM in most regions. It varied slightly with retinal location (χ2(9) = 58.8, p < 0.0001), but it was not affected by individual eye (χ2(9) = 10.7, p = 0.29). RNFB visibility showed good agreement between graders (ICC 0.89, 95%CI 0.87–0.91), and excellent repeatability (ICC 0.96–0.99). Depth range of visible RNFBs was highly correlated with RNFLT (ρ = 0.9, 95%CI: 0.86–0.95). The range of depths with visible RNFBs varies markedly across the healthy retina, consistently with RNFLT. To extract all RNFB information consistently across the retina, slab properties should account for differences across retinal locations and between individual eyes. / This work was supported by a College of Optometrists Research Fellowship (JD).