Caractérisation biomécanique expérimentale du tissu pulmonaire avec et sans agrafes afin de caractériser le phénomène de fuite d’air apparaissant à la suite d’une résection pulmonaire

Pour traiter les patients atteints d'un cancer du poumon, les chirurgiens thoraciques retirent la tumeur cancéreuse à l’aide d’une agrafeuse chirurgicale. À la suite de cette opération de résection pulmonaire, 28-60% des patients développent une fuite d’air. Cette fuite engendre une augmentation de la durée d’hospitalisation et une augmentation des coûts de soins de santé. Au niveau clinique, la résection des lobes supérieurs entraine des fuites plus conséquentes que la résection des lobes inférieurs. Une seule étude numérique corrobore ce constat clinique et l’explique comme résultant d’une augmentation de la contrainte sur le tissu pulmonaire restant post-résection, qui doit s’adapter à la forme en ogive de la cage thoracique. Très peu d’études se sont intéressées à étudier la cause de ces fuites, cependant quelques études expérimentales déclarent que la fuite se produirait aux extrémités de la ligne d’agrafe et qu’elle serait de nature biomécanique. Ce projet a donc pour objectif de caractériser biomécaniquement et visuellement les tissus pulmonaires avec et sans agrafes afin d'acquérir des connaissances sur les fuites d'air après une résection pulmonaire. Un banc expérimental a été conçu pour ventiler mécaniquement 11 poumons porcins frais ex vivo. La ventilation cyclique se fait par une pompe à seringue contrôlée en pression remplie d'air. Un microcontrôleur contrôle et enregistre la pression pulmonaire et le volume d'air pompé. Simultanément, deux stéréo-caméras capturent des images à intervalles réguliers de la surface costale déformée des poumons. Les images brutes sont ensuite utilisées pour calculer les déplacements et les déformations tridimensionnelles à l'aide de la méthode de corrélation d'images digitales. Une première caractérisation a permis d’identifier où se présente la fuite d’air par une observation visuelle et une documentation par photographie de poumons immergés et ventilés. Une deuxième investigation a permis de contrôler puis mesurer les pressions et les volumes en tout temps pour identifier les lobes les plus propices à la fuite ainsi que les conséquences du retrait d’un lobe sur la mécanique pulmonaire via l’évaluation de la compliance (variation de volume en réponse à une variation de pression). Enfin, une combinaison novatrice de la technique de corrélation d’images digitales appliquée sur les poumons ventilés a permis de comparer les patrons de déformation principale, avant et après agrafage, pour déterminer une possible correspondance entre la localisation des fuites et la zone de déformation principale maximale. Les résultats montrent notamment que la fuite d’air se développe au niveau des trous des pattes des agrafes du rang intérieur de la ligne d’agrafe, suite à un déchirement de la plèvre de la surface costale qui expose le tissu pulmonaire. Le lobe inférieur fuit statistiquement plus facilement, i.e. à des pressions moins élevées (p-value<0.046), que le lobe supérieur même dans des conditions ex vivo. Ce résultat concorde avec les observations cliniques et celles de l’étude numérique mais offre aussi un complément d’information puisque le résultat existe même sans l’influence de la cage thoracique. Les conséquences de la chirurgie de résection est évaluée par la compliance. Elle diminue seulement de 9 % entre l’état sain et les états réséqués. Ce résultat contraire à la littérature qui associe la diminution de compliance au volume de tissu réséqué. Enfin, l’étude des patrons de déformation principal montrent que le poumon gonfle en priorité au niveau de ses bords en développant une déformation 6 fois plus élevée que le tissu situé proche de l’arrivée d’air. L’étude des patrons de déformation en cisaillement montre une répartition non homogène de cisaillements non nul : le poumon ne se déforme pas de manière équibiaxiale comme un ballon de fête. Enfin, la comparaison des mesures de déformation principale avec les localisations de fuites semble corroborer l’hypothèse que la fuite se développe à la suite d’une fracture de la plèvre annoncée par un maximum de déformation proche de la ligne d’agrafe. Ces résultats suggèrent que les patrons de déformations sont essentiels pour comprendre les mécanismes de rupture de la ligne d’agrafe et devraient faire l'objet d'une enquête plus approfondie. Ce travail expérimental caractérise avec précision la physiologie des fuites d'air post-résection pulmonaire. Il fournit de nouvelles données à la littérature sur les changements de la compliance pulmonaire, à basse pression, sous ventilation par pression positive. D'autres études devraient viser à valider ces résultats à différentes pressions de ventilation. Les conclusions liées à ces études pourraient influencer les pratiques de pression appliquées aux drains thoraciques postopératoires déjà controversées. L’utilisation de la corrélation d’images digitales appliquée à l’ensemble du poumon est novatrice et fournit des résultats pertinents sur la biomécanique pulmonaire. Les patrons de déformation sont donc essentiels pour comprendre les mécanismes de fuites d’air au niveau des lignes d'agrafes et devraient faire l'objet d'études plus approfondies.----------ABSTRACT To treat patients with lung cancer, thoracic surgeons remove the cancerous tumor using a surgical stapler. Following this lung resection operation, 28-60% of patients develop an air leak. This leakage leads to an increase in the length of hospitalization and increased health care costs. Clinically, resections of upper lobes result in more leakage than resections of lower lobes. A single numerical study corroborates this clinical finding and explains it as a result of increased stress on the remaining lung tissue after resection, which has to adapt to fit the ogive shape of the rib cage. Very few studies have investigated the cause of these leaks, however a few experimental studies state that leaks would occur at the extremities of staple lines and would be biomechanical in nature. The objective of this project is therefore to biomechanically and visually characterize lung tissue with and without staples in order to gain knowledge about air leaks after lung resection. An experimental bench was designed to mechanically ventilate 11 fresh porcine lungs ex vivo. Cyclic ventilation is performed by a pressure-controlled syringe pump filled with air. A microcontroller monitors and records lung pressure and volume of air pumped. Simultaneously, two stereo-cameras capture images at regular intervals of the deformed costal surface of the lungs. The raw images are then used to calculate the three-dimensional displacements and deformations using the Digital Image Correlation method. An initial characterization has identified where air leakage occurs by visual observation and photographic documentation of immersed and ventilated lungs. A second investigation made it possible to control and measure pressures and volumes at all times to identify the lobes most likely to leak as well as the consequences of lobectomies on lung mechanics by calculating lungs compliance (variation of volume in response to a variation of pressure). Finally, an innovative combination of the digital image correlation technique applied to ventilated lungs has made it possible to compare the principal strain patterns, before and after stapling, to determine a possible relationship between the location of leaks and the zone of maximum principal strain. In particular, air leaks develop at staple holes from inner row of staple line, as a result of torn visceral pleura on the costal surface exposing lung tissue. Lower lobes statistically leak more easily, i.e. at lower pressures (p-value<0.046), than upper lobes even under ex vivo conditions. This result is consistent with the clinical and numerical study observations but also provides additional information since it exists even without the influence of the rib cage. The consequences of the resection surgery are evaluated by compliance. It decreases only by 9 % between healthy and resected states. This result is contrary to the literature which associates the decrease in compliance with the volume of resected tissue. Finally, the study of principal strain patterns shows that lung inflates primarily at its edges, developing a strain 6 times higher than the tissue located near the air supply. The study of shear strain patterns shows a non-homogeneous distribution of non-zero shear strains: lung does not deform equibiaxially like a party balloon. Finally, the comparison of principal strain patterns with observed leak locations seems to corroborate our hypothesis that the leak develops following a fracture of the pleura announced by a maximum principal strain close to the staple line. These results suggest that strain patterns are essential to understanding the staple line failure mechanisms and should be further investigated. This experimental work accurately characterizes the physiology of air leaks after lung resection. It provides new data to the literature on changes in lung compliance at low pressure under positive pressure ventilation. Further studies should aim to validate these results at different ventilation pressures. These studies findings may influence the already controversial pressure practices applied to postoperative chest drains supposed to reduce the leak. The use of digital image correlation applied to the entire lung is innovative and provides relevant results on lung biomechanics. Strain patterns are therefore essential for understanding the mechanisms of air leaks at staple lines and should be further investigated

Recent advances in human respiratory epithelium models for drug discovery

The respiratory epithelium is intimately associated with the pathophysiologies of highly infectious viral contagions and chronic illnesses such as chronic obstructive pulmonary disorder, presently the third leading cause of death worldwide with a projected economic burden of £1.7 trillion by 2030. Preclinical studies of respiratory physiology have almost exclusively utilised non-humanised animal models, alongside reductionistic cell line-based models, and primary epithelial cell models cultured at an air-liquid interface (ALI). Despite their utility, these model systems have been limited by their poor correlation to the human condition. This has undermined the ability to identify novel therapeutics, evidenced by a 15% chance of success for medicinal respiratory compounds entering clinical trials in 2018. Consequently, preclinical studies require new translational efficacy models to address the problem of respiratory drug attrition. This review describes the utility of the current in vivo (rodent), ex vivo (isolated perfused lungs and precision cut lung slices), two-dimensional in vitro cell-line (A549, BEAS-2B, Calu-3) and three-dimensional in vitro ALI (gold-standard and co-culture) and organoid respiratory epithelium models. The limitations to the application of these model systems in drug discovery research are discussed, in addition to perspectives of the future innovations required to facilitate the next generation of human-relevant respiratory models

Evaluation of a Patient-Specific, Low-Cost, 3-Dimensional–Printed Transesophageal Echocardiography Human Heart Phantom

Simulation based education has been shown to increase the task-specific capability of medical trainees. Transesophageal echocardiography training greatly benefits from the use of simulators. They allow real time scanning of a beating heart and generation of ultrasound images side by side with anatomically accurate virtual model. These simulators are costly and have many limitations. 3D printing technologies have enabled the creation of bespoke phantoms capable of being used as task-trainers. This study aims to compare the ease of use and accuracy of a low-cost patient-specific, Computer-tomography based, 3D printed, echogenic TEE phantom compared to a commercially available echocardiography training mannequin. We hypothesized that a low-cost, 3D printed custom-made, cardiac phantom has comparable image quality, accuracy and usability as existing commercially available echocardiographic phantoms. After Institutional Ethic Research Board approval, we recruited ten American Board – Certified cardiac anesthesiologists and conducted a blinded comparative study divided into two stages. Stage one consisted of image assessment. A set of basic TEE views obtained from the 3D printed and commercial phantom were presented to the participants on a computer screen in random order. For each image, participants will be asked to identify the view, identify the quality of the image on a 1-5 Likert scale compared to the corresponding human view and guess with which phantom it was acquired (1 not at all realistic to patients view and 5 realistic to patients view). Stage two, participants will be asked to use the 3D printed and the commercially available phantom to obtain basic TEE views. In a maximum of 30 minutes. Each view was recorded and assessed for accuracy by two certified echocardiographers. Time needed to acquire each basic view and number of correct views was recorded. Overall usability of the phantoms was assessed through a questionnaire. For all continuous variables, we will calculate mean, median and standard deviation. We use Wilcoxon Signed-Rank test to assess significant differences in the rating of each phantom. All ten participants completed all part of the study. All participants could recognize all of the standard views. The average Likert scale was 3.2 for the 3D printed and 2.9 for the commercial Phantom with no significant difference. The average time to obtain views was 24.5 and 30 sec for the 3D printed and the commercial phantoms respectively statistically significantly in favor of the 3D printed phantom. The qualitative user assessment for ease to obtain the views, probe manipulation, image quality and overall experience were in great favor of the 3D printed phantom. Our Study suggest that the quality of TEE images obtained on the 3D printed phantom are not significantly different from those obtained on the commercial Phantom. The ease of use and time required to complete a basic TEE exam were in favor of the 3D Printed phantom.:Table of Content 1. Bibliographic Description 3 2. Introduction 4 2.1. Perioperative transesophageal echocardiography 4 2.2. Transesophageal echocardiography training 5 2.3. Transesophageal echocardiography simulation 6 2.4. 3D Heart Printing 13 2.5. 3D Segmentation 16 2.6. Development of the study phantom 17 2.7. Study Rationale 18 3. Publication 22 4. Summary 30 5. References 33 6. Appendices 37 6.1. Darstellung des eigenes Beitrags 38 6.2. Erklärung über die eigenständige Abfassung der Arbeit 39 6.3. Lebenslauf 40 6.4. Publikationen und Vorträge 44 6.5. Danksagung 61

VAD in failing Fontan: simulation of ventricular, cavo-pulmonary and biventricular assistance in systolic/diastolic ventricular dysfunction and in pulmonary vascular resistance increase.

Aim: Due to the lack of donors, VADs could be an alternative to heart transplantation for Failing Fontan patients (PTs). Considering the complex physiopathology and the type of VAD connection, a numerical model (NM) could be useful to support clinical decisions. The aim of this work is to test a NM simulating the VADs effects on failing Fontan for systolic dysfunction (SD), diastolic dysfunction (DD) and pulmonary vascular resistance increase (PRI). Methods: Data of 10 Fontan PTs were used to simulate the PTs baseline using a dedicated NM. Then, for each PTs a SD, a DD and a PRI were simulated. Finally, for each PT and for each pathology, the VADs implantation was simulated. Results: NM can well reproduce PTs baseline. In the case of SD, LVAD increases the cardiac output (CO) (35%) and the arterial systemic pressure (ASP) (25%). With cavo-pulmonary assistance (RVAD) a decrease of inferior vena cava pressure (IVCP) (39%) was observed with 34% increase of CO. With the BIVAD an increase of ASP (29%) and CO (37%) was observed. In the case of DD, the LVAD increases CO (42%), the RVAD decreases the IVCP. In the case of PRI, the highest CO (50%) and ASP (28%) increase is obtained with an RVAD together with the highest decrease of IVCP (53%). Conclusions: The use of NM could be helpful in this innovative field to evaluate the VADs implantation effects on specific PT to support PT and VAD selection

Front Lines of Thoracic Surgery

Front Lines of Thoracic Surgery collects up-to-date contributions on some of the most debated topics in today's clinical practice of cardiac, aortic, and general thoracic surgery,and anesthesia as viewed by authors personally involved in their evolution. The strong and genuine enthusiasm of the authors was clearly perceptible in all their contributions and I'm sure that will further stimulate the reader to understand their messages. Moreover, the strict adhesion of the authors' original observations and findings to the evidence base proves that facts are the best guarantee of scientific value. This is not a standard textbook where the whole discipline is organically presented, but authors' contributions are simply listed in their pertaining subclasses of Thoracic Surgery. I'm sure that this original and very promising editorial format which has and free availability at its core further increases this book's value and it will be of interest to healthcare professionals and scientists dedicated to this field

Major Abdominal Surgical Complications : Innovative Approaches

In this thesis the focus was on three major complications after abdominal surgery: incisional hernia (IH), prolonged postoperative ileus (PPOI), and colorectal anastomotic leakage (CAL). The results were summarized in three parts: _Part 1_ focused on prediction and detection of these surgical complications; _Part 2_ describes different methods to prevent complications; _Part 3_ analyzed also prevention of major surgical complications with a focus on patients at risk. Even anno 2017 it is still necessary to explore new strategies to prevent complications in abdominal surgery. Also with new surgical techniques, for example the use of staplers for colorectal anastomosis, prevention of CAL is still an issue. In addition, early detection of a complication is necessary to prevent from worse. This also requires more attention and research since detection of leakage is still mainly based on clinical observation and the experience of the surgeon. Research on more advanced technical and/ or digital solutions to objectively assess and quantify leakage and other complications is strongly needed. Therefore in this thesis the focus was to develop different strategies that may facilitate prevention, prediction, and diagnosis of different important abdominal surgical complications such as colorectal anastomotic leakage, postoperative ileus, incisional hernia, and infectious complications