Littérature scientifique sur le sujet « Multi-organ-on-chip »

This review is an introduction into the world of organ-on-chip models. By briefly explaining the concept of microfluidics and ‘lab-on-chip’, the main focus is on organs-on-chip and body-on-a-chip. The usual method to test the toxicity of a drug is through animal testing. However, the results do not always correlate to humans. In order to avoid animal testing, but also attain useful results, human-derived cell cultures using microfluidics have gained attention. Among all the different types of organ-on-chip devices, this review focuses on three distinct organs: heart, skin and liver. The main requirements for each organ-on-chip, as well as recent researches are presented. There have been considerable advancements with organ-on-chip models; however, even these have their limitations. Due to the fact that the system mimics a single organ, the systemic effect of drugs cannot be fully tested. Therefore, body-on-a-chip systems have been developed; which basically are a composed of a single chip that has several chambers, each chamber accounting for a distinct organ. Multi-organ-on-chip systems have been investigated, and even commercialized, the field still being under extensive research.

Abstract The in vitro simulation of organs resolves the accuracy, ethical, and cost challenges accompanying in vivo experiments. Organoids and organs-on-chips have been developed to model the in vitro, real-time biological and physiological features of organs. Numerous studies have deployed these systems to assess the in vitro, real-time responses of an organ to external stimuli. Particularly, organs-on-chips can be most efficiently employed in pharmaceutical drug development to predict the responses of organs before approving such drugs. Furthermore, multi-organ-on-a-chip systems facilitate the close representations of the in vivo environment. In this review, we discuss the biosensing technology that facilitates the in situ, real-time measurements of organ responses as readouts on organ-on-a-chip systems, including multi-organ models. Notably, a human-on-a-chip system integrated with automated multi-sensing will be established by further advancing the development of chips, as well as their assessment techniques.

Translational Organ-on-Chip Platform (TOP) is a multi-institutional effort to develop an open platform for automated organ-on-chip culture that actively facilitates the integration of components from various developers.

The liver is a key organ that can communicate with many other districts of the human body. In the last few decades, much interest has focused on the interaction between the liver and the gut microbiota, with their reciprocal influence on biosynthesis pathways and the integrity the intestinal epithelial barrier. Dysbiosis or liver disorders lead to0 epithelial barrier dysfunction, altering membrane permeability to toxins. Clinical and experimental evidence shows that the permeability hence the delivery of neurotoxins such as LPS, ammonia and salsolinol contribute to neurological disorders. These findings suggested multi-organ communication between the gut microbiota, the liver and the brain. With a view to in vitro modeling this liver-based multi-organ communication, we describe the latest advanced liver-on-a-chip devices and discuss the need for new organ-on-a-chip platforms for in vitro modeling the in vivo multi-organ connection pathways in physiological and pathological situations.

With advantageous features such as minimizing the cost, time, and sample size requirements, organ-on-a-chip (OOC) systems have garnered enormous interest from researchers for their ability for real-time monitoring of physical parameters by mimicking the in vivo microenvironment and the precise responses of xenobiotics, i.e., drug efficacy and toxicity over conventional two-dimensional (2D) and three-dimensional (3D) cell cultures, as well as animal models. Recent advancements of OOC systems have evidenced the fabrication of ‘multi-organ-on-chip’ (MOC) models, which connect separated organ chambers together to resemble an ideal pharmacokinetic and pharmacodynamic (PK-PD) model for monitoring the complex interactions between multiple organs and the resultant dynamic responses of multiple organs to pharmaceutical compounds. Numerous varieties of MOC systems have been proposed, mainly focusing on the construction of these multi-organ models, while there are only few studies on how to realize continual, automated, and stable testing, which still remains a significant challenge in the development process of MOCs. Herein, this review emphasizes the recent advancements in realizing long-term testing of MOCs to promote their capability for real-time monitoring of multi-organ interactions and chronic cellular reactions more accurately and steadily over the available chip models. Efforts in this field are still ongoing for better performance in the assessment of preclinical attributes for a new chemical entity. Further, we give a brief overview on the various biomedical applications of long-term testing in MOCs, including several proposed applications and their potential utilization in the future. Finally, we summarize with perspectives.

The modular-based multi-organ-on-a-chip enables more stable and flexible configuration to better mimic the complex biological phenomena for versatile biomedical applications. However, the existing magnetic-based interconnection modes are mainly realized by directly embedding and/or fixing magnets into the modular microfluidic devices for single use only, which will inevitably increase the complexity and cost during the manufacturing process. Here, we present a novel design of a reusable standardized universal interface module (RSUIM), which is highly suitable for generic organ-on-chip applications and their integration into multi-organ systems. Both pasting-based and clamping-based interconnection modes are developed in a plug-and-play manner without fluidic leakage. Furthermore, due to the flexibility of the modular design, it is simple to integrate multiple assembled modular devices through parallel configuration into a high throughput platform. To test its effectiveness, experiments on the construction of both the microvascular network and vascularized tumor model are performed by using the integration of the generic vascularized organ-on-a-chip module and pasting-based RSUIM, and their quantitative analysis results on the reproducibility and anti-cancer drug screening validation are further performed. We believe that this RSUIM design will become a standard and critical accessory for a broad range of organ-on-a-chip applications and is easy for commercialization with low cost.

Depuis 4 décennies, un modèle intermédiaire entre les traditionnelles approches in vivo et in vitro émerge : les Systèmes MicroPhysiologiques (SMP). Ils sont construits pour recréer différents niveaux de physiologie humaine, du simple organe à leurs interactions. Ils améliorent l’environnement de culture grâce à des microstructures accueillant des modèles d’architecture 3D et multicellulaire, et intègrent des microcapteurs monitorant l’activité cellulaire et leur environnement.Ce nouvel outil d’investigation est d’intérêt pour la recherche fondamentale sur les maladies comme le diabète. Dans le cas de cette maladie incurable, la régulation du glucose sanguin, résultant d’interactions complexes entre les îlots pancréatiques, le foie, les adipocytes et les muscles, est altérée. Un Multi-Organe-sur-Puce (MOsP) est un SMP pouvant reproduire ces interactions, et représente donc un modèle pertinent pour la recherche sur le diabète. En effet, la régulation inter-organe n’est pas entièrement reproduite par les modèles in vitro usuels, et requiert de multiples capteurs, ce qui est éthiquement et techniquement impossible in vivo. Dans le contexte du diabète, il n’existe aucun MOsPs reproduisant l’action des îlots sur les muscles, malgré l’importance des muscles squelettiques dans la régulation glycémique.Cette thèse propose une méthodologie pour construire un MOsP étudiant les interactions d’îlot à muscle dans la régulation glycémique. Les 3 objectifs du MOsP étaient : atteindre des concentrations physiologiques d’insuline grâce à des îlots sécrétant en réponse à une élévation physiologique de glucose, induisant une prise de glucose mesurable par les muscles, et monitorer l’expérience en direct. Pour cela, les investigations ont été menées avec une approche interdisciplinaire, utilisant et confrontant des résultats venant d’expériences biologiques in vitro et de simulations modélisant la biologie et la physique.Ce manuscrit détaille les étapes de la méthodologie, et délivre différents designs pour progressivement construire un MOsP comprenant: une puce microfluidique contenant les cellules et un capteur de glucose connecté directement au flux. Les principales découvertes ont été :- Un milieu et procédure de co-culture entre îlots primaires et LHCN-M2 myotubes ont été démontrés.- Un substrat de culture commun de type MicroElectrodes Array a été trouvé.- Des îlots ont été cultivés en puce microfluidique, et ont présenté une sécrétion d’insuline en réponse au glucose durant des expériences en fluidique. Des myotubes ont pu se différentier en puce, et ont présenté une prise de glucose basale (insuline indépendant).- Une stratégie in vitro-in silico pour dimensionner le MOsP a été développée et implémentée. Un modèle in silico simplifié d’îlot a été développé pour rapidement explorer 2 designs de puce. Des expériences in vitro correspondantes, de sécrétion d’insuline, ont été menées et confrontées aux expériences in silico. Les résultats ont soulevé l’hypothèse que les îlots n’avaient pas une fonctionnalité optimale dans nos petits volumes de culture. La même constatation a été faite concernant les myotubes, où la prise de glucose insuline dépendante a été démontrée en macro volumes, mais en micro volumes, la réponse observée (uniquement à concentration physiologique d’insuline) doit être reproduite avec des expériences plus robustes pour démontrer leur présence.- Un capteur de glucose compatible avec le système microfluidique a été caractérisé à l’aide d’expériences in vitro et in silico.- Un multi-potentiostat a été développé dans la perspective de futures mesures électrochimiques multiples et intégrées.Les bases et perspectives présentées ici permettront d’achever le MOsP îlot-muscle par de futurs travaux. La méthodologie peut aussi être réutilisée pour l’ajout de nouveaux organes (foie, adipocytes) complétant le MOsP, qui permettra de mieux comprendre les dérégulations intervenant dans le diabète de type 2
Over the past 4 decades, an intermediate model between the traditional in vivo and in vitro approaches has emerged: the MicroPhysiological Systems (MPS). MPS are designed to recapitulate different levels of human physiology, from the single organ to organs crosstalk. They upgrade the culture environment by patterning microstructures hosting 3D and multicellular architecture models and integrate microsensors monitoring cell activity and environment.This new investigation tool is of interest in fundamental research on diseases such as diabetes. In this incurable disease, blood glucose regulation, resulting from a complex organs interplay between the pancreatic islets, the liver, the adipocytes and the muscles, is impaired. A Multi-Organ-on-a-Chip (MOoC) is a MPS that can recapitulate these organs crosstalk and represents a relevant model for diabetes research. Indeed, inter-organ regulations are not recapitulated by usual in vitro models, and deciphering these interactions requires multiple sensors, which is not ethically and technically possible in vivo. In the context of diabetes, MOoCs reproducing the islets to skeletal muscles communication do not exist so far, despite the importance of the skeletal muscles impact on blood glucose, under islets action.In this thesis, we propose a methodology to design a MOoC deciphering islets to muscles interactions in blood glucose regulation. The MOoC objectives were to: (i) attain physiological insulin concentration secreted by islets in response to physiological glucose elevation, (ii) that induces a measurable glucose uptake by the muscle cells, (iii) monitor online relevant parameters. To that end, the investigations were conducted with an interdisciplinary approach, using and confronting results from both in vitro biological experiments and in silico modelling of biology and physics.This manuscript details the methodology steps, delivering different designs for progressive validation toward a complete MOoC that comprises a microfluidic chip with cells and an online glucose sensor. During the MOoC construction, our main findings were the following:- A co-culture medium and procedure for primary islets and LHCN-M2 myotubes were demonstrated.- A common MicroElectrodes Array-based substrate was found suited for co-culture in a single microfluidic chip.- Islets were cultured in microfluidic chips, and presented an insulin secretory response to glucose during fluidic experiments. Myotubes were successfully differentiated in microfluidic chips, and presented a measurable basal (insulin-independent) glucose uptake.- An in silico and in vitro informed MOoC scaling strategy was developed and implemented. A simplified in silico islet model was developed to rapidly explore chip designs. Corresponding in vitro insulin secretion experiments were conducted and confronted to the in silico experiments. Results raised the hypothesis that islets function was sub optimal when cultured in our low volume. Similar observation was made concerning myotubes scaling, where insulin-dependent glucose uptake was demonstrated in macro volumes experiments, but in micro volumes, the observed insulin response (only at physiological insulin concentration) has to be further repeated with improved experiments to explicitly demonstrate its presence.- A glucose biosensor compatible with microfluidic was characterized under different injection protocols, using in vitro and in silico experiments.- A multi-potentiostat was developed in the perspective of multiple and integrated electrochemical sensing in the MOoC.From the grounds and perspectives presented in this thesis, future work can be conducted to further complete this islet-muscle MOoC. The methodology can be re-used and extended in the perspective of adding new organs (liver, adipocytes) in this MOoC in order to better address the interorgan crosstalk deregulations in type 2 diabetes pathophysiology

L’urbanisation et la mondialisation sont des phénomènes de société qui multiplient et complexifient les sources de pollution. Parmi elles, la pollution atmosphérique impacte notablement la santé humaine à l’échelle mondiale de par son caractère transfrontière. L’appareil respiratoire est une voie d’absorption de nombreux xénobiotiques, sous forme de gaz, d’aérosols ou de nanoparticules. Une fois dans les voies respiratoires, les substances inhalées sont susceptibles d’interagir avec les cellules pulmonaires. Les mécanismes par lesquels des xénobiotiques inhalés induisent des dommages pulmonaires sont complexes, notamment en raison de l’hétérogénéité cellulaire des poumons. En raison de cette complexité, les modèles animaux constituent un outil de référence pour les études toxicologiques prédictives, cependant, dans le contexte européen de réduction de l’expérimentation animale (REACH, et les règles 3R), le développement de méthodes alternatives fiables est devenu une nécessité. Les modèles in vitro sont de bons candidats car plus simple et moins couteux à mettre en oeuvre que les modèles vivo et permettent de travailler avec des cellules ou des tissus d’origine humaine ce qui contribue à améliorer la pertinence des résultats. Cependant, l’extrapolation limitée du vitro au vivo est souvent liée à un manque de complexité des modèles, notamment en raison de l’absence de communication inter-organes. Les technologies des multi-organes sur puce cherchent à surmonter ces limitations en connectant plusieurs organoïdes métaboliquement actifs au sein d’un même circuit de culture afin de reproduire des interactions de type systémiques. Dans ce contexte, nous décrivons un modèle permettant de connecter in vitro, par le biais de la microfluidique, une barrière pulmonaire (voie d’entrée des xénobiotiques inhalés) à un organe détoxifiant tel que le foie, afin d’évaluer la toxicité liée à un stress inhalatoire de façon plus systémique. Cette approche permet de considérer la biotransformation des composés inhalés et l’interaction inter-organes comme possible modulateurs de la toxicité. Le projet étant dans les premières phase de développement, la robustesse expérimentale était au coeur du projet. L’objectif principal était de prouver qu’une substance modèle était capable de transiter dans le dispositif, au travers des deux compartiments tissulaires, afin de pouvoir étudier la dynamique inter-organes poumon/foie en condition de stress xénobiotique. Le projet a été articulé en trois phases expérimentales : - Caractérisation des réponses biologiques spécifiques aux tissus pulmonaire et hépatique en réponse à un stress. La viabilité, la fonctionnalité et les activités métaboliques des monocultures ont été évaluées après exposition à une substance modèle. - Adaptation et préparation des monocultures aux conditions de co-culture afin de préserver la viabilité et la fonctionnalité des tissus. - Les compartiments pulmonaire et hépatique ont été cultivés jointement dans un circuit de culture microfluidique fermé. La co-culture a été exposée à une substance modèle à travers la barrière pulmonaire afin d’imiter un mode d’exposition inhalatoire. Les paramètres de viabilité et de fonctionnalité des tissus ont été évalué post-culture afin de mettre en évidence quelconque phénomène d’interaction inter-organe. La caractérisation du modèle de co-culture a été réalisé grâce à l’exposition d’un agent hépatotoxique de référence, largement étudié dans la littérature : l’acétaminophène aussi connu sous le nom de paracétamol (APAP). L’exposition à la barrière pulmonaire n’est pas physiologique mais permet d’observer quantitativement le passage et la circulation du xénobiotique à travers le dispositif car l’APAP interfère avec la viabilité et les performances métaboliques hépatique, permettant ainsi de vérifier que le compartiment hépatique peut avoir accès à l’exposition effectuée à travers la barrière pulmonaire
Urbanization and globalization are prevailing social phenomena that multiply and complexify the sources of modern pollution. Amongst others, air pollution has been recognized as an omnipresent life-threatening hazard, comprising a wide range of toxic airborne xenobiotics that expose man to acute and chronic threats. The defense mechanisms involved in hazardous exposure responses are complex and comprise local and systemic biological pathways. Due to this complexity, animal models are considered prime study models. However, in light of animal experimentation reduction (3Rs), we developed and investigated an alternative in vitro method to study systemic-like responses to inhalationlike exposures. In this context, a coculture platform was established to emulate interorgan crosstalks between the pulmonary barrier, which constitutes the route of entry of inhaled compounds, and the liver, which plays a major role in xenobiotic metabolism. Both compartments respectively comprised a Calu-3 insert and a HepG2/C3A biochip which were jointly cultured in a dynamically-stimulated environment for 72 hours. The present model was characterized using acetaminophen (APAP), a well-documented hepatotoxicant, to visibly assess the passage and circulation of a xenobiotic through the device. Two kinds of models were developed: (1) the developmental model allowed for the technical setup of the coculture, and (2) the physiological-like model better approximates a vivo environment. Based on viability, and functionality parameters the developmental model showed that the Calu-3 bronchial barrier and the HepG2/C3A biochip can successfully be maintained viable and function in a dynamic coculture setting for 3 days. In a stress-induced environment, present results reported that the coculture model emulated active and functional in vitro crosstalk that seemingly was responsive to high (1.5 and 3 mM) and low (12 and 24 μM) xenobiotic exposure doses. Lung/liver crosstalk induced modulation of stress response dynamics, delaying cytotoxicity, proving that APAP fate, biological behaviors and cellular stress responses were modulated in a broader systemic-like environment

Abstract The organ-on-a-Chip (OOC) concept appeared intending to increase the efficiency and effectiveness of R&D activities, and open doors to precision and personalized medicine. However, for such devices to provide adequate results, they must mimic a specific human microenvironment with great accuracy. In the present work, a computational model of an organ-on-a-chip model was developed and optimized by evaluating the effectiveness and characteristics of some optimization methods. To perform the optimization and simulation, a geometry appropriate to the needs was first designed, having in base the current literature. After that, a mesh set capable of maintaining a balance between the accuracy of the results and computational performance was generated and a mesh study was conducted. Then, the simulation and optimization were performed. The latter was conducted by applying two different methods, the Multi-Objective Genetic Algorithm (MOGA) and Nonlinear Programming by Quadratic Lagrangian (NLPQL), for later comparison of results. Bearing in mind the hemodynamics in the liver, the goal of this optimization was to minimize the organ model blood flow mean velocity, in order to allow the adequate transfer of substances between the blood and liver cells.