L’émergence de nouvelles sources ambiantes d’ionisation rendent possible l’étude par spectrométrie de masse d’échantillons natifs, sans préparation nécessaire. En combinaison avec des méthodes d’échantillonnage, elles permettent l’identification de biomolécules en conservant leur localisation histologique. Dans ce contexte, nous avons développé deux outils de micro-échantillonnage pour la caractérisation de tissus biologiques. Le 1er est basé sur l’ablation laser par une source impulsionnelle à 532 nm suivie de la capture en goutte du matériel ablatée. Nous avons démontré que l'analyse de biomolécules capturées était possible malgré leur faible absorbance à cette longueur d’onde. Ceci est dû à l’existence d’un mécanisme d’ablation induit par le substrat qui se substitue au processus d’ablation directe entre le laser et l’échantillon irradié. Cette stratégie a été appliquée avec succès à l’étude de protéines et de lipides sur tissu. Le 2nd est un nouvel instrument d’analyse de biomolécules en temps réel. Basé sur l’ablation laser à 2,94 µm - en coïncidence avec une bande d’absorption intense de l’eau - et couplé au spectromètre de masse par un tube d’aspiration, il permet la caractérisation de tissus biologiques ex vivo et in vivo. Les profils moléculaires générés correspondent à des métabolites et des lipides. Le caractère faiblement invasif et indolore de l’irradiation laser a été démontré lors d’études in vivo sur des phalanges d’individus volontaires. Le potentiel de ce dispositif est finalement démontré par une application clinique, le cancer de l’ovaire et le développement de banques de données de profils moléculaires correspondant aux différents grades de la pathologie. / Recent advances in ambient ionization sources enable the study by mass spectrometry (MS) of native samples, without any preparation. In combination with sampling methods, they allow identification of biomolecules with respect to their histological localization. In this context, we have developed and explored the potential of two micro-sampling tools for the characterization of biological tissues. The first one consists in the ablation of analytes from biological sample using a ns laser at 532 nm and their subsequent capture in a solvent droplet which can then be analyzed by MS. We demonstrate that analyses are possible, despite the low absorbance of the biological material at this wavelength. This is due to the preponderance of an indirect substrate-mediated ablation mechanism which contrasts with the conventional direct ablation driven by analyte absorption. The second tool is an instrument for real-time analysis of biomolecules. Based on the laser ablation at 2.94 µm in coincidence with a strong absorption band of the water, and coupled to the spectrometer by a transfer line, it provides the ex vivo and in vivo characterization of biological tissue. Molecular profiles generated in real-time show signals corresponding to metabolites and lipids. The low-invasive and virtually painless nature of the laser irradiation was demonstrated through in vivo studies on phalanges of voluntary individuals. Finally, some of the developments made on this tool was dedicated for a clinical application, namely the ovarian cancer, and the development of the databases of molecular profiles corresponding to different grades of the disease.

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archives@tulane.edu / We have developed a laser-biomaterial interaction-based prototyping platform capable of three fabrication modes: (1) laser direct write of cells, microbeads, and other biomaterials; (2) fabrication of cell encapsulating microspheres (microcapsules); and (3) laser micromachining of substrates. Using this system, we are able to precisely place biomaterials, such as cells, into substrates with spatial constraints from laser micromachining or wholly fabricate scaffolds that are cell laden. This enables fabrication of cocultures in almost any geometry and controlled gradients of chemical factors. In addition, the process is parallelizable, thus allowing for numerous potential bioassay applications. One such assay is a differential system for quantifying multiple outcomes in response to multiple parallel biophysicochemical cues in competition. These novel assays are complex, reproducible, and disposable microenvironments. This document will summarize the control integration developed for Laser Direct Write, a 2D model of laser ablation, with a computational method demonstrating preliminary results. Finally the biofabrication methods discussed are applied to an Organ-on-a-Chip model to develop a fully automated fabrication process. / 1 / samuel sklare

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The mechanical tools currently used in orthopedic and dental surgery are imprecise and may cause heat damage. Ultrashort pulse lasers are a promising replacement, but their ablation efficiency must be improved. The goal of this thesis was to achieve high ablation efficiency, precision, and minimal collateral damage using an ultrafast laser on bovine hard tissue. This work used two types of lasers: a Ti:Sapphire laser (210 fs, 800 nm, 1 kHz) and a fiber laser (1 ps, 1035 nm, 100 kHz - 1 MHz). This thesis begins with a review of the literature on laser-tissue interactions and the effect of certain laser parameters on the ablation process. The next section uses a Ti:Sapphire laser and bovine bone to explore the properties of laser-tissue interactions, including ablation threshold and incubation coefficient. Results showed that as the number of incident pulses goes up, ablation threshold goes down. The threshold range went from 1.08 ± 0.15 J/cm2 at 25 incident pulses to 0.73 ± 0.12 J/cm2 at 1000 pulses. The incubation coefficient, S, was calculated to be 0.90 ± 0.02. The relationship between ablation depth and fluence, scanning speed, and number of successive passes was characterized as a first step towards preparing large-cavity with high removal efficiency using a Ti:Sapphire and fiber lasers. Depth increased with fluence and number of passes, but it decreased with scanning speed. The influence of environmental conditions including air, compressed air flow, still water and flowing water on cavity ablation depth, and rate was investigated using a Ti:Sapphire laser with aim to enhance ablation efficiency. Findings showed that the deepest cavities and fastest ablation rates were achieved with compressed air flow. Air flow also resulted in the most precise cuts, the smoothest surfaces, and the absence of microcracks. This thesis also used a fiber laser to explore the effect of fluence and repetition rate on removal rate and ablation quality. Results indicated that ablation rate increases with fluence and pulse rate. When the repetition rate exceeded 600 kHz, the laser caused thermal and mechanical damage, indicated by the presence of amorphous carbon. The effect of environmental conditions and laser parameters such as repetition rate provide valuable insights into the ultrafast laser ablation mechanisms for medicine and biology field. / Thesis / Doctor of Philosophy (PhD)

La fibrillation atriale (FA) est le trouble du rythme cardiaque le plus fréquent et dont la prévalence est en constante augmentation. Les extrasystoles déclenchant cette arythmie naissent le plus souvent des veines pulmonaires. Ainsi l’ablation des veines pulmonaires est devenue un traitement important de cette arythmie, surtout quand elle est paroxystique. Cependant le maintien de la FA est assuré par du substrat atrial pathologique.Le traitement endocavitaire de ce substrat comprend essentiellement l’ablation de potentielsfragmentés enregistrés en FA.Nous avons démontré que ces potentiels fragmentés existent aussi en rythme sinusal etqu’une partie de ces potentiels pouvait être générée par une activation vagale myocardiquelocale.Par ailleurs cette ablation de FA présente de nombresuses complications dont certaines sont potentiellement graves comme par exemple la tamponnade.Nous avons montré que la ponction transseptale nécessaire pour réaliser cette intervention pouvait être effectuée de manière sure en utilisant un monitorage du septum interatrial parechocardiographie endovasculaire utilisée par voie oesophagienne, diminuant ainsi le risque de tamponnade.Nous avons aussi montré que la présence d’une récidive d’arythmie précoce (<1 mois) postablationétait hautement prédictive d’une récidive tardive et qu’une réablation précoce dansle mois suivant la première intervention était efficace mais nécessitait un nombre plusimportant de procédures pour obtenir une efficacité stable dans le tempsPar ailleurs, nous avons montré que l’ablation de FA générait une importante inflammation systémique et que cette inflammation était associée à un taux plus faible de récidives précoces mais non tardives.Enfin nous avons montré qu’un cycle fibrillatoire rapide< 142 ms, une ancienneté de la FA >21 mois et une amplitude de l’onde fibrillatoire < 0.07 mV étaient des facteurs importants d’échec d’ablation de FA persistante. / Pas de résumé anglais

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Clinical hyperthermia refers to treatment of tumors by heating the lesions between 40 and 45° C. Several clinical trials have demonstrated that hyperthermia provides significant improvements in clinical outcomes for a variety of tumors, especially when combined with radiotherapy. However, its routine clinical application is still not optimal and major improvements are needed. The temperature distributions achieved are far from satisfactory and improved temperature control and monitoring are still in need of further development. The use of gold nanoparticles (GNPs) has emerged as a good method to achieve local heat delivery when combined with near-infrared (NIR) laser. GNPs have a plasmon resonance frequency that can be tuned to absorb strongly in the NIR region where tissue absorption of laser light is minimal, allowing for less tissue heating and better penetration. For further development of the technique and appropriate clinical translation, it is essential to have a computational method by which the temperature distribution within the tumor and surrounding tissue can be estimated. Previously, our group developed a technique to estimate the temperature increase in a GNP-filled medium, by taking into account the heat generated from individual GNPs. This method involved a two-step approach combining the temperature rise due to GNPs and the solution to the heat equation using the laser light as heat source. The goal of this project was to develop a one-step approach that calculates the temperature distribution using the solution to the heat equation with multiple heat source terms, the laser light, and each individual GNP. This new method can be of great use in developing a treatment planning technique for GNP-mediated thermal therapy including hyperthermia.