A versatile, compartmentalised gut-on-a-chip system for pharmacological and toxicological analyses

A novel, integrated, in vitro gastrointestinal (GI) system is presented to study oral bioavailability parameters of small molecules. Three compartments were combined into one hyphenated, flow-through set-up. In the first compartment, a compound was exposed dynamically to enzymatic digestion in three consecutive microreactors, mimicking the processes of the mouth, stomach, and intestine. The resulting solution (chyme) continued to the second compartment, a flow-through barrier model of the intestinal epithelium allowing absorption of the compound and metabolites thereof. The composition of the effluents from the barrier model were analysed either offline by electrospray-ionisation-mass spectrometry (ESI-MS), or online in the final compartment using chip-based ESI-MS. Two model drugs, omeprazole and verapamil, were used to test the integrated model. Omeprazole was shown to be broken down upon treatment with gastric acid, but reached the cell barrier unharmed when introduced to the system in a manner emulating an enteric-coated formulation. In contrast, verapamil was unaffected by digestion. Finally, a reduced uptake of verapamil was observed when verapamil was introduced to the system dissolved in apple juice, a simple food matrix. It is envisaged that this integrated, compartmentalised GI system has potential for enabling future research in the fields of pharmacology, toxicology, and nutrition

Model-Based Analysis of User Behaviors in Medical Cyber-Physical Systems

Human operators play a critical role in various Cyber-Physical System (CPS) domains, for example, transportation, smart living, robotics, and medicine. The rapid advancement of automation technology is driving a trend towards deep human-automation cooperation in many safety-critical applications, making it important to explicitly consider user behaviors throughout the system development cycle. While past research has generated extensive knowledge and techniques for analyzing human-automation interaction, in many emerging applications, it remains an open challenge to develop quantitative models of user behaviors that can be directly incorporated into the system-level analysis. This dissertation describes methods for modeling different types of user behaviors in medical CPS and integrating the behavioral models into system analysis. We make three main contributions. First, we design a model-based analysis framework to evaluate, improve, and formally verify the robustness of generic (i.e., non-personalized) user behaviors that are typically driven by rule-based clinical protocols. We conceptualize a data-driven technique to predict safety-critical events at run-time in the presence of possible time-varying process disturbances. Second, we develop a methodology to systematically identify behavior variables and functional relationships in healthcare applications. We build personalized behavior models and analyze population-level behavioral patterns. Third, we propose a sequential decision filtering technique by leveraging a generic parameter-invariant test to validate behavior information that may be measured through unreliable channels, which is a practical challenge in many human-in-the-loop applications. A unique strength of this validation technique is that it achieves high inter-subject consistency despite uncertain parametric variances in the physiological processes, without needing any individual-level tuning. We validate the proposed approaches by applying them to several case studies

Efficient design of precision medical robotics

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2012.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (p. 106-114).Medical robotics is increasingly demonstrating the potential to improve patient care through more precise interventions. However, taking inspiration from industrial robotics has often resulted in large, sometimes cumbersome designs, which represent high capital and per procedure expenditures, as well as increased procedure times. This thesis proposes and demonstrates an alternative model and method for developing economical, appropriately scaled medical robots that improve care and efficiency, while moderating costs. Key to this approach is a structured design process that actively reduces complexity. A selected medical procedure is decomposed into discrete tasks which are then separated into those that are conducted satisfactorily and those where the clinician encounters limitations, often where robots' strengths would be complimentary. Then by following deterministic principles and with continual user participation, prototyping and testing, a system can be designed that integrates into and assists with current procedures, rather than requiring a completely new protocol. This model is expected to lay the groundwork for increasing the use of hands-on technology in interventional medicine.by Nevan Clancy Hanumara.Ph.D

Student Research Colloquium Proceedings 2011

2011 Student Research Colloquium proceedings include the following: explanation of the Student Research Colloquium passport , a schedule of the day\u27s events, acknowledgement of research sponsors, the day\u27s program, formal paper competition participants; poster presentation participants; conference presentation abstracts, student presenter index, research sponsor index, planning committee, poster and paper presentation judges, registration desk, sponsors, and donors, map of Atwood Memorial Center. Keynote Address: Brianda Cediel, Executive Director, Hands Across the World: Research with an International Flair : In this talk, Cediel takes the lessons she has learned during her remarkable 28 year teaching career with people of different countries and diverse ethnicities. She came back to SCSU in 2000 to finish her studies in ESL (English as a Second Language). Journey with her through those years and learn how she became the founder of Hands Across the World , a very successful program for immigrants here in St. Cloud, MN. The program is recognized at a national level as one of the best for refugees and immigrants. She serves her students with compassion, love, empathy, and humility. Her commitment to the program\u27s vision is to empower and enable those around her while pulling them to thrive in the global community. We are proud to welcome Brianda Cediel to her alma mater

Electronic nose implementation for biomedical applications

The growing rate of diabetes and undiagnosed diabetes related diseases is becoming a worldwide major health concern. The motivation of this thesis was to make use of a technology called the ‘electronic nose’ (eNose) for diagnosing diseases. It presents a comprehensive study on metabolic and gastro-intestinal disorders, choosing diabetes as a target disease. Using eNose technology with urinary volatile organic compounds (VOCs) is attractive as it allows non-invasive monitoring of various molecular constituents in urine. Trace gases in urine are linked to metabolic reactions and diseases. Therefore, urinary volatile compounds were used for diagnosis purposes in this thesis. The literature on existing eNose technologies, their pros and cons and applications in biomedical field was thoroughly reviewed, especially in detecting headspace of urine. Since the thesis investigates urinary VOCs, it is important to discover the stability of urine samples and their VOCs in time. It was discovered that urine samples lose their stability and VOCs emission after 9 months. A comprehensive study with 137 diabetic and healthy control urine samples was done to access the capability of commercially available eNose instruments for discrimination between these two groups. Metal oxide gas sensor based commercial eNose (Fox 4000, AlphaMOS Ltd) and field asymmetric ion mobility spectrometer (Lonestar, Owlstone Ltd) were used to analyse volatiles in urinary headspace. Both technologies were able to distinguish both groups with sensitivity and specificity of more than 90%. Then the project moved onto developing a Non-dispersive infrared (NDIR) sensor system that is non-invasive, low-cost, precise, rapid, simple and patient friendly, and can be used at both hospitals and homes. NDIR gas sensing is one of the most widely used optical gas detection techniques. NDIR system was used for diagnosing diabetes and gastro related diseases from patient’s wastes. To the best of the authors’ knowledge, this is the first and only developed tuneable NDIR eNose system. The developed optical eNose is able to scan the whole infrared range between 3.1μm and 10.5 μm with step size of 20 nm. To simulate the effect of background humidity and temperature on the sensor response, a gas test rig system that includes gas mixture, VOC generator, humidity generator and gas analyser was designed to enable the user to have control of gas flow, humidity and temperature. This also helps to find out system’s sensitivity and selectivity. Finally, after evaluating the sensitivity and selectivity of optical eNose, it was tested on simple and complex odours. The results were promising in discriminating the odours. Due to insufficient sample batches received from the hospital, synthetic urine samples were purchased, and diabetic samples were artificially made. The optical eNose was able to successfully separate artificial diabetic samples from non-diabetic ones

Developing preclinical devices for neuroscience research in the fields of animal tracking, fMRI acquisition, and 3D histology cutting

[ES] La neurociencia es un campo que abarca muchas especialidades. El objetivo de esta tesis es subsanar algunas carencias tecnológicas que existen en los métodos actuales de experimentación animal en neurociencia. En esta tesis, se presentan seis proyectos, que tendrán como objetivo mejorar el "Principio de las tres R", el cual fue enunciado por los biólogos ingleses W. M. S. Russell y R. L. Burch, durante la experimentación animal. El comportamiento es uno de los aspectos más importantes de la vida animal. Depende de los vínculos entre los animales, sus sistemas nerviosos y sus entornos. Para estudiar el comportamiento de los animales de laboratorio, se necesitan varias herramientas, pero una herramienta de seguimiento es esencial para llevar a cabo un estudio de comportamiento exhaustivo. Varias herramientas de seguimiento visual están actualmente disponibles. Sin embargo, todas tienen algunos inconvenientes. Por ejemplo, en una situación en la que un animal está dentro de una madriguera o cerca de otros animales, las cámaras de rastreo (tracking) no siempre pueden detectar la ubicación precisa o el movimiento del animal. Por esta razón, los entornos enriquecidos para intentar recrear el hábitat natural de los animales en experimentación no pueden utilizarse, ya que los datos recopilados son insuficientes/inexactos. Con la finalidad de mejorar los experimentos de tracking RFID Assisted Tracking Tile (RATT) es presentado en esta tesis. RATT es un sistema de seguimiento basado en tecnología de identificación pasiva de radiofrecuencia (RFID) y está compuesto por baldosas electrónicas con las que se puede construir una gran superficie, sobre la cual los animales pueden moverse libremente. Esto permite la identificación más precisa de los animales, así como el seguimiento de sus movimientos. Este sistema, que también se puede combinar con un sistema de seguimiento con cámaras, allana el camino para estudios completos de comportamiento en entornos enriquecidos. Dada la capacidad de rastrear animales y, por lo tanto, realizar experimentos de comportamiento exhaustivos, es posible observar cómo se comportan los sujetos desde un punto de vista externo. Sin embargo, si queremos comprender lo que sucede en el cerebro de estos sujetos, es necesario aplicar otras técnicas de análisis, por ejemplo, el estudio de señales dependientes del nivel de oxígeno en la sangre (BOLD, por sus siglas en inglés). Las señales BOLD se basan en las respuestas vasculares a la activación neuronal y se utilizan ampliamente en estudios de investigación clínicos y preclínicos. En entornos preclínicos, los animales suelen ser anestesiados. Sin embargo, los anestésicos causan cambios en la fisiología de los animales, p. Ej. hipotermia, y esto tiene el potencial de alterar las señales funcionales de MRI (fMRI). Para evitar la hipotermia en roedores anestesiados, se presenta TherMouseDuino. Este es un sistema de control automático de temperatura de código abierto, que reduce las fluctuaciones de la temperatura, lo que proporciona condiciones sólidas para realizar experimentos de resonancia magnética funcional. En los cursos de biología y neurociencia, la anatomía del cerebro se enseña generalmente utilizando imágenes de resonancia magnética (IRM) o secciones histológicas de diferentes planos. Estos muestran las áreas macroscópicas más importantes en el cerebro de un animal. Sin embargo, este método no es dinámico ni intuitivo. En esta tesis se presenta un cerebro de rata impreso en 3D con fines educativos. La manipulación manual de la estructura, facilitada por la ampliación de sus dimensiones, junto con la capacidad de desmontar el "cerebro" en algunas de sus partes principales, facilita la comprensión de la organización 3D del sistema nervioso. Este es un método alternativo y mejorado para enseñar a los estudiantes en general y a los biólogos, en particular, la anatomía del cerebro de rata.[CA] La neurociència és un camp que abasta moltes especialitats. L'objectiu d'aquesta tesi és esmenar algunes manques tecnològiques que existeixen en els mètodes actuals d'experimentació animal en neurociència. En aquesta tesi, es presenten sis projectes, que tindran com a objectiu millorar el "Principi de les tres R", el qual va ser enunciat pels biòlegs anglesos W. M. S. Russell i R. L. Burch, durant l'experimentació animal. El comportament és un dels aspectes m'és importants de la vida animal. Depèn dels vincles entre els animals, els seus sistemes nerviosos i els seus entorns. Per estudiar el comportament dels animals de laboratori, es necessiten diverses eines, però` una eina de seguiment és essencial per a dur a terme un estudi de comportament exhaustiu. Diverses eines de seguiment visual estan actualment disponibles. No obstant això, totes tenen alguns inconvenients. Per exemple, en una situació en la qual un animal esta` dins d'un cau o prop d'altres animals, les cambres de rastreig (tracking) no sempre poden detectar la ubicació precisa o el moviment de l'animal. Per aquesta raó, els entorns enriquits per a intentar recrear l'hàbitat natural dels animals en experimentació no poden utilitzar-se, ja que les dades recopilades són insuficients/inexactes. Amb la finalitat de millorar els experiments de tracking/seguiment RFID Assisted Tracking Tile (RATT) és presentat en aquesta tesi. RATT es un sistema de seguiment basat en tecnologia d'identificació passiva de radiofreqüència (RFID) i esta` compost per rajoles electròniques amb les quals es pot construir una gran superfície, sobre la qual els animals poden moures lliurement. Això permet la identificació més precisa dels animals, així com el seguiment dels seus moviments. Aquest sistema, que també es pot combinar amb un sistema de seguiment amb cambres, aplana el camí per a estudis complets de comportament en entorns enriquits. Donada la capacitat de rastrejar animals i, per tant, realitzar experiments de comportament exhaustius, és possible observar com es comporten els subjectes des d'un punt de vista extern. No obstant això, si volem comprendre el que succeeix en el cervell d'aquests subjectes, és necessari aplicar altres tècniques d'anàlisis, per exemple, l'estudi de senyals dependents del nivell d'oxigen en la sang (BOLD, per les seues sigles en anglès). Els senyals BOLD es basen en les respostes vasculars a l'activació neuronal i s'utilitzen àmpliament en estudis d'investigació clínics i preclínics. En entorns preclínics, els animals solen ser anestesiats. No obstant això, els anestèsics causen canvis en la fisiologia de els animals, per exemple hipotèrmia, i això te el potencial d'alterar els senyals funcionals de MRI (fMRI). Per a evitar la hipotèrmia en rosegadors anestesiats, es presenta TherMouseDuino. Aquest és un sistema de control automàtic de temperatura de codi obert, que redueix les fluctuacions de la temperatura, la qual cosa proporciona condicions solides per a realitzar experiments de ressonància magnètica funcional. En els cursos de biologia i neurociència, l'anatomia del cervell s'ensenya generalment utilitzant imatges de ressonància magnètica (IRM) o seccions histològiques de diferents plans. Aquests mostren les àrees macroscòpiques més importants en el cervell de un animal. No obstant això, aquest mètode no és dinàmic ni intuïtiu. En aquesta tesi es presenta un cervell de rata imprès en 3D amb finalitats educatius. La manipulació manual de l'estructura, facilitada per l'ampliació de les seues dimensions, juntament amb la capacitat de desmuntar el "cervell" en algunes de les seues parts principals, facilita la comprensió de l'organització 3D del sistema nerviós. Aquest és un mètode alternatiu i millorat per a ensenyar a els estudiants en general i als biòlegs, en particular, l'anatomia del cervell de rata.[EN] Neuroscience is a field that covers many specialties. The objective of this thesis is to correct some technological deficiencies that exist in current methods of animal experimentation in neuroscience. In this thesis, six projects are presented, which will aim to improve the "Principle of the three Rs" in animal experimentation enunciated by the English biologists W. M. S. Russell and R. L. Burch. In the present era of impressive progress in neuroscience, it is still not arguable that a complete understanding of the brain cannot be possible without a comparable understanding of animal behavior. In order to study the behavior of laboratory animals, various tools are needed, being a reliable tracking system one of the most important to follow large populations of individual subjects that interact in complex manners. Several visual tracking tools are currently available. However, they all have some drawbacks. For example, in a situation where an animal is inside a cave, or is in close proximity to other animals, tracking cameras cannot always detect the precise location or movement of the animal. For this reason, environments that have been enriched in order to attempt to recreate the natural habitat of the animals under experiment, cannot be used, as the data gathered is insufficient/inaccurate. In order to improve the current tracking systems , the RATT is presented. RATT is a tracking system based on passive RFID technology and it is composed of electronic tiles. Using several tiles, a large surface area, on which the animals can move freely, can be built. This enables the more accurate identification of the animals, as well as the tracking of their movements. This system, which can also be combined with a visual tracking system, paves the way for complete behavioral studies in enriched environments. Given the ability to track animals and thus conduct thorough behavioral experiments, it is possible to observe how the subjects behave from an external viewpoint. However, if we want to understand what is going on in the brains of these subjects, it is necessary to apply other analysis techniques, for example the study of BOLD signals. BOLD signals are based on vascular responses to neuronal activation and are used extensively in clinical and preclinical research studies. In preclinical settings, animals are usually anesthetized. However, anesthetics cause changes in the physiology of the animals, e.g. hypothermia, and this has the potential to disrupt fMRI signals. In order to avoid hypothermia in anesthetized rodents, TherMouseDuino is presented. This is an Open-Source automatic temperature control system, which reduces temperature fluctuations, thus providing robust conditions in which to perform fMRI experiments. In biology and neuroscience courses, brain anatomy is generally taught using MRI or histological sections of different planes. These show the most important macroscopic areas in an animals' brain. However, this method is neither dynamic nor intuitive. An anatomical 3D printed rat brain with educative purposes is presented in this thesis. Hand manipulation of the structure, facilitated by the scaling up of its dimensions, together with the ability to dismantle the "brain" into some of main its constituent parts, facilitates the understanding of the 3D organization of the nervous system. This is an alternative and improved method for teaching students in general and biologists, in particular, the rat brain anatomy.This work was supported in part by the Spanish Ministerio de Economía y Competitividad (MINECO) and FEDER funds under grants BFU2015-64380-C2-2-R (D.M.) and BFU2015-64380-C2-1-R, by EU Horizon 2020 Program 668863-SyBil-AA grant (S.C.). S.C. acknowledges financial support from the Spanish State Research Agency, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (ref. SEV-2013-0317) and by a grant “Ayudas para la formación de personal investigador (FPI)” from the Vicerrectorado de Investigación, Innovación y Transferencia of the Universitat Politècnica de València.Quiñones Colomer, DR. (2019). Developing preclinical devices for neuroscience research in the fields of animal tracking, fMRI acquisition, and 3D histology cutting [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/118795TESI