A Molecular Communication Scheme to Estimate the State of Biochemical Processes on a Lab-on-a-Chip

International audienceA key application of advanced spectroscopy methods is to estimate equilibrium states of biochemical processes in situ and in vivo. Nevertheless, an often present difficulty is the requirement that the biochemical process and its environment (such as the substrate) satisfy special conditions. One means of resolving this issue is to communicate information about the equilibrium states of the biochemical process to another location, supported via microfluidic channles within a lab-on-a-chip. In this paper, we develop a signaling strategy and estimation algorithms for equilibrium states of a biochemical process. For a toggle-switch circuit model important in cellular differentiation studies, we study via simulation the tradeoff between the rate of obtaining spectroscopy measurements and the estimation error, providing insights into requirements of spectroscopy devices for high-throughput biological assays. CCS CONCEPTS • Applied computing → Health care information systems; • Computing methodologies → Model verification and validation; Mixture modeling

Molecular Communication for Equilibrium State Estimation in Biochemical Processes on a Lab-on-a-Chip

International audienceA basic problem in molecular biology is to estimate equilibrium states of biochemical processes. To this end, advanced spectroscopy methods have been developed in order to estimate chemical concentrations in situ or in vivo. However, such spectroscopy methods can require special conditions that do not allow direct observation of the biochemical process. A natural means of resolving this problem is to transmit chemical signals to another location within a lab-on-a-chip device; that is, employing molecular communication in order to perform spectroscopy in a different location. In this paper, we develop such a signaling strategy and estimation algorithms for equilibrium states of a biochemical process. In two biologically-inspired models, we then study via simulation the tradeoff between the rate of obtaining spectroscopy measurements and the estimation error, providing insights into requirements of spectroscopy devices for highthroughput biological assays

Microwave resonant sensors

Microwave resonant sensors use the spectral characterisation of a resonator to make high sensitivity measurements of material electromagnetic properties at GHz frequencies. They have been applied to a wide range of industrial and scientific measurements, and used to study a diversity of physical phenomena. Recently, a number of challenging dynamic applications have been developed that require very high speed and high performance, such as kinetic inductance detectors and scanning microwave microscopes. Others, such as sensors for miniaturised fluidic systems and non-invasive blood glucose sensors, also require low system cost and small footprint. This thesis investigates new and improved techniques for implementing microwave resonant sensor systems, aiming to enhance their suitability for such demanding tasks. This was achieved through several original contributions: new insights into coupling, dynamics, and statistical properties of sensors; a hardware implementation of a realtime multitone readout system; and the development of efficient signal processing algorithms for the extraction of sensor measurements from resonator response data. The performance of this improved sensor system was verified through a number of novel measurements, achieving a higher sampling rate than the best available technology yet with equivalent accuracy and precision. At the same time, these experiments revealed unforeseen applications in liquid metrology and precision microwave heating of miniature flow systems.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Developments in dynamic field gradient focusing: microfluidics and integration

Advances in modern science require the development of more robust and improved systems for electroseparations in chromatography. In response, the progress of a new analytical platform is discussed. DFGF (Dynamic Field Gradient Focusing) is a separation technique, first described in 1998, which exploits the differences in electrophoretic mobility and hydrodynamic area of analytes to result in separation. This is achieved by taking a channel and applying a hydrodynamic flow in one direction and a counteracting electric field gradient acting in the opposite direction, resulting in analytes reaching a focal point according to their electrophoretic mobility. Work through this project has seen innovations to improve existing DFGF devices, including the design and manufacture of a novel packing material, while developing the latest DFGF system. This incorporates a microfluidic separation channel, eliminating the need for packing material or monolith. The new microfluidic device also features whole-on-column UV detection. Improvements through the developments of this device are discussed, most notably the utilisation of a new rapid prototyping technique. Examples of applications undertaken with the new device are demonstrated including novel samples and integration with mass spectrometry and 2D-HPLC

Microwave resonant sensors

Microwave resonant sensors use the spectral characterisation of a resonator to make high sensitivity measurements of material electromagnetic properties at GHz frequencies. They have been applied to a wide range of industrial and scientific measurements, and used to study a diversity of physical phenomena. Recently, a number of challenging dynamic applications have been developed that require very high speed and high performance, such as kinetic inductance detectors and scanning microwave microscopes. Others, such as sensors for miniaturised fluidic systems and non-invasive blood glucose sensors, also require low system cost and small footprint. This thesis investigates new and improved techniques for implementing microwave resonant sensor systems, aiming to enhance their suitability for such demanding tasks. This was achieved through several original contributions: new insights into coupling, dynamics, and statistical properties of sensors; a hardware implementation of a realtime multitone readout system; and the development of efficient signal processing algorithms for the extraction of sensor measurements from resonator response data. The performance of this improved sensor system was verified through a number of novel measurements, achieving a higher sampling rate than the best available technology yet with equivalent accuracy and precision. At the same time, these experiments revealed unforeseen applications in liquid metrology and precision microwave heating of miniature flow systems

Microfluidic systems for neuronal cell culture

At a high level of abstraction, the brain is a system for analysing sensory information, and responding appropriately. That information is encoded and stored in the millions of neural circuits that comprise the brain. Deciphering this code is essential to understanding how memories are implemented in physiologically normal brain tissue, and to inferring the nature of some neurological disorders affecting memory such as Alzheimer’s disease, in which the neural encoding is aberrant or unsuccessful. One approach to this problem is to reduce the complexity of the brain functionality to three elements: stimuli, response, and reinforcement. The electrical activity of individual neurons can be recorded with electrodes, capturing the pathways of signal propagation in a network of cells. Individual neurons can be also induced to reliably respond to electrical or optical stimuli, so that they initiate, relay, or even block a signal. If the stimuli to a finite network of cells can be made heterogeneous so that only a sub-population of cells is targeted, then the network can be trained to react in a repeatable way to a given stimulus, testing the concept that the higher order functions of the brain can emerge from a simple set of underlying computational rules. Training however requires a mechanism for reinforcing only some of the possible pathways, in synchrony with stimuli and in response to the recorded network activity. In the intact brain, this mechanism is pharmacological: a neuromodulator such as dopamine is released throughout the brain, but as it only coincides with some but not all neuronal activity, the reinforcement is temporally selective. The key task of this project is to emulate this selective neuromodulator reinforcement in vitro in a finite neuronal network. The project must also provide capacity for heterogeneous stimulation and individual cell recording, which can be coordinated with the reinforcement under computer control. The strategy used was to develop microscale chambers to house a small network of cultured neurons. The chambers were integrated with existing cell recording and stimulating technologies, so that specific connections between neurons could be both monitored and induced. Neuronal cultures of a few hundred cells were successfully grown in microchannels, on substrates capable of recording their electrical activity. Thus it was possible to create a small cultured network in which complete network activity could be detected, subject to a sufficiently precise recording technique. Additionally, a fluid-handling system was developed in order to emulate the continual replenishment of nutrients and soluble gases that are essential to cell survival. The system is intended to deliver soluble chemicals that modulate neuronal activity, on a timescale that is consistent with neuromodulator delivery in the body. The fluid handling system comprises a set of pressure driven pumps under automated computer control. This system has the capacity to deliver neuromodulator in solution with high spatiotemporal precision. The ability to reliably deliver and wash off precise volumes of drugs in a matter of seconds, with no dilution of the intended concentration, will be of great benefit to researchers investigating the response of various cell types to different agonists

Nanochips and medical applications

Ο όρος «νανοτσιπ» αναφέρεται σε ένα ολοκληρωμένο κύκλωμα (τσιπ) με νανοϋλικά και δομές στη νανοκλίμακα (1-100nm). Ένα ολοκληρωμένο κύκλωμα είναι μια συλλογή ηλεκτρονικών εξαρτημάτων, όπως τρανζίστορ, δίοδοι, πυκνωτές και αντιστάσεις. Τα σημερινά τρανζίστορ είναι στη νανοκλίμακα, αλλά μπορούν να τροποποιηθούν με νανοδομές για την κατασκευή βιοαισθητήρων που μπορούν να πραγματοποιούν ανίχνευση βιομορίων, όπως ιόντα, μόρια DNA, αντισώματα και αντιγόνα με μεγάλη ευαισθησία. Υλικά και Μέθοδοι: Πραγματοποιήθηκε συστηματική αναζήτηση βιβλιογραφίας με χρήση των ηλεκτρονικών βάσεων δεδομένων PubMed, Google Scholar και Scopus για την ανάπτυξη και χρήση νανοτσίπ σε ιατρικές εφαρμογές. Για τον προσδιορισμό των σχετικών εργασιών, τα κριτήρια συμπερίληψης αναφέρονται σε άρθρα στην αγγλική γλώσσα, άρθρα βιβλιογραφικού περιεχομένου ή/και έρευνών. Τα κριτήρια αποκλεισμού ήταν άρθρα εφημερίδων, περιλήψεις συνεδρίων και επιστολές. Αποτελέσματα: Τεχνικές in-vivo και in-vitro έχουν χρησιμοποιηθεί για την ανίχνευση μορίων DNA, ιόντων, αντισωμάτων, σημαντικών πρωτεϊνών και καρκινικών δεικτών, όχι μόνο από δείγματα αίματος αλλά και από ιδρώτα, σάλιο και άλλα βιολογικά υγρά. Διαγνωστική εφαρμογή των νανοτσίπ αποτελεί και η ανίχνευση πτητικών οργανικών ενώσεων μέσω τεστ εκπνεόμενης αναπνοής. Υπάρχουν και αρκετές θεραπευτικές εφαρμογές αυτών των συσκευών ημιαγωγών όπως τσιπ διασύνδεσης εγκεφάλου-υπολογιστή για παραλυτικές ή επιληπτικές καταστάσεις, κατασκευή «βιονικών» οργάνων όπως τεχνητός αμφιβληστροειδής, τεχνητό δέρμα και ρομποτικά προθετικά άκρα για ακρωτηριασμένους ή ρομποτική χειρουργική. Συμπέρασμα: Η χρήση των νανοτσίπ στην ιατρική είναι ένας αναδυόμενος τομέας με αρκετές θεραπευτικές εφαρμογές όπως η διάγνωση, η παρακολούθηση της υγείας και της φυσικής κατάστασης και η κατασκευή «βιονικών» οργάνων.Background: The term “nanochip” pertains to an integrated circuit (chip) with nanomaterials and components in the nano-dimension (1-100nm). An integrated circuit is essentially a collection of electronic components, like transistors, diodes, capacitors, and resistors. Current transistors are in the nanoscale but can also be modified with nanostructures like nanoribbons and nanowires to manufacture biosensors that can perform label-free, ultrasensitive detection of biomolecules like ions, DNA molecules, antibodies and antigens. Materials and Methods: A systematic literature search was conducted using the electronic databases PubMed, Google Scholar and Scopus for the development and use of nanochips in medical applications. For the identification of relevant papers, the inclusion criteria referred to articles in the English language, review and/or research articles. The exclusion criteria were newspaper articles, conference abstracts and letters. Results: In-vivo and In-vitro techniques have been used for detection of DNA molecules, ions, antibodies, important proteins, and tumor markers, not only from blood samples but also from sweat, saliva and other biological fluids. Another diagnostic application of nanochips is detection of volatile organic compounds via a breath test. There are also several therapeutic applications of these semiconductor devices like brain-computer interface chips for paralytic or epileptic conditions, manufacture of “bionic” organs like artificial retinas, artificial skin and robotic prostheses for amputees or robotic surgery. Conclusion: The use of nanochips in medicine is an emerging field with several therapeutic applications like diagnostics, health and fitness monitoring, and manufacture of “bionic” organs

Microfluidic systems for neuronal cell culture

At a high level of abstraction, the brain is a system for analysing sensory information, and responding appropriately. That information is encoded and stored in the millions of neural circuits that comprise the brain. Deciphering this code is essential to understanding how memories are implemented in physiologically normal brain tissue, and to inferring the nature of some neurological disorders affecting memory such as Alzheimer’s disease, in which the neural encoding is aberrant or unsuccessful. One approach to this problem is to reduce the complexity of the brain functionality to three elements: stimuli, response, and reinforcement. The electrical activity of individual neurons can be recorded with electrodes, capturing the pathways of signal propagation in a network of cells. Individual neurons can be also induced to reliably respond to electrical or optical stimuli, so that they initiate, relay, or even block a signal. If the stimuli to a finite network of cells can be made heterogeneous so that only a sub-population of cells is targeted, then the network can be trained to react in a repeatable way to a given stimulus, testing the concept that the higher order functions of the brain can emerge from a simple set of underlying computational rules. Training however requires a mechanism for reinforcing only some of the possible pathways, in synchrony with stimuli and in response to the recorded network activity. In the intact brain, this mechanism is pharmacological: a neuromodulator such as dopamine is released throughout the brain, but as it only coincides with some but not all neuronal activity, the reinforcement is temporally selective. The key task of this project is to emulate this selective neuromodulator reinforcement in vitro in a finite neuronal network. The project must also provide capacity for heterogeneous stimulation and individual cell recording, which can be coordinated with the reinforcement under computer control. The strategy used was to develop microscale chambers to house a small network of cultured neurons. The chambers were integrated with existing cell recording and stimulating technologies, so that specific connections between neurons could be both monitored and induced. Neuronal cultures of a few hundred cells were successfully grown in microchannels, on substrates capable of recording their electrical activity. Thus it was possible to create a small cultured network in which complete network activity could be detected, subject to a sufficiently precise recording technique. Additionally, a fluid-handling system was developed in order to emulate the continual replenishment of nutrients and soluble gases that are essential to cell survival. The system is intended to deliver soluble chemicals that modulate neuronal activity, on a timescale that is consistent with neuromodulator delivery in the body. The fluid handling system comprises a set of pressure driven pumps under automated computer control. This system has the capacity to deliver neuromodulator in solution with high spatiotemporal precision. The ability to reliably deliver and wash off precise volumes of drugs in a matter of seconds, with no dilution of the intended concentration, will be of great benefit to researchers investigating the response of various cell types to different agonists

2020 Student Symposium Research and Creative Activity Book of Abstracts

The UMaine Student Symposium (UMSS) is an annual event that celebrates undergraduate and graduate student research and creative work. Students from a variety of disciplines present their achievements with video presentations. It’s the ideal occasion for the community to see how UMaine students’ work impacts locally – and beyond. The 2020 Student Symposium Research and Creative Activity Book of Abstracts includes a complete list of student presenters as well as abstracts related to their works

Evolvable Smartphone-Based Point-of-Care Systems For In-Vitro Diagnostics

Recent developments in the life-science -omics disciplines, together with advances in micro and nanoscale technologies offer unprecedented opportunities to tackle some of the major healthcare challenges of our time. Lab-on-Chip technologies coupled with smart-devices in particular, constitute key enablers for the decentralization of many in-vitro medical diagnostics applications to the point-of-care, supporting the advent of a preventive and personalized medicine. Although the technical feasibility and the potential of Lab-on-Chip/smart-device systems is repeatedly demonstrated, direct-to-consumer applications remain scarce. This thesis addresses this limitation. System evolvability is a key enabler to the adoption and long-lasting success of next generation point-of-care systems by favoring the integration of new technologies, streamlining the reengineering efforts for system upgrades and limiting the risk of premature system obsolescence. Among possible implementation strategies, platform-based design stands as a particularly suitable entry point. One necessary condition, is for change-absorbing and change-enabling mechanisms to be incorporated in the platform architecture at initial design-time. Important considerations arise as to where in Lab-on-Chip/smart-device platforms can these mechanisms be integrated, and how to implement them. Our investigation revolves around the silicon-nanowire biological field effect transistor, a promising biosensing technology for the detection of biological analytes at ultra low concentrations. We discuss extensively the sensitivity and instrumentation requirements set by the technology before we present the design and implementation of an evolvable smartphone-based platform capable of interfacing lab-on-chips embedding such sensors. We elaborate on the implementation of various architectural patterns throughout the platform and present how these facilitated the evolution of the system towards one accommodating for electrochemical sensing. Model-based development was undertaken throughout the engineering process. A formal SysML system model fed our evolvability assessment process. We introduce, in particular, a model-based methodology enabling the evaluation of modular scalability: the ability of a system to scale the current value of one of its specification by successively reengineering targeted system modules. The research work presented in this thesis provides a roadmap for the development of evolvable point-of-care systems, including those targeting direct-to-consumer applications. It extends from the early identification of anticipated change, to the assessment of the ability of a system to accommodate for these changes. Our research should thus interest industrials eager not only to disrupt, but also to last in a shifting socio-technical paradigm