INTEGRATION OF CMOS TECHNOLOGY INTO LAB-ON-CHIP SYSTEMS APPLIED TO THE DEVELOPMENT OF A BIOELECTRONIC NOSE

This work addresses the development of a lab-on-a-chip (LOC) system for olfactory sensing. The method of sensing employed is cell-based, utilizing living cells to sense stimuli that are otherwise not easily sensed using conventional transduction techniques. Cells have evolved over millions of years to be exquisitely sensitive to their environment, with certain types of cells producing electrical signals in response to stimuli. The core device that is introduced here is comprised of living olfactory sensory neurons (OSNs) on top of a complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC). This hybrid bioelectronic approach to sensing leverages the sensitivity of OSNs with the electronic signal processing capability of modern ICs. Intimately combining electronics with biology presents a number of unique challenges to integration that arise from the disparate requirements of the two separate domains. Fundamentally the obstacles arise from the facts that electronic devices are designed to work in dry environments while biology requires not only a wet environment, but also one that is precisely controlled and non-toxic. Design and modeling of such heterogeneously integrated systems is complicated by the lack of tools that can address the multiple domains and techniques required for integration, namely IC design, fluidics, packaging, and microfabrication, and cell culture. There also arises the issue of how to handle the vast amount of data that can be generated by such systems, and specifically how to efficiently identify signals of interest and communicate them off-chip. The primary contributions of this work are the development of a new packaging scheme for integration of CMOS ICs into fluidic LOC systems, a methodology for cross-coupled multi-domain iterative modeling of heterogeneously integrated systems, demonstration of a proof-of-concept bioelectronic olfactory sensor, and a novel event-based technique to minimize the bandwidth required to communicate the information contained in bio-potential signals produced by dense arrays of electrically active cells

Heterogeneously integrated impedance measuring system with disposable thin-film electrodes

We propose a novel integrated impedance measurement system with disposable thin-film electrodes. Most modern CMOS-based biosensors use on-chip electrodes to interface between the electronics and biosamples, which forces disposal of the CMOS chip after a few measurements, since most biological reactions are non-reversible. The sensor performance is also limited by the design of on-chip electrodes due to the physical dimensions and the CMOS design rules restrictions. In this work, we extract the electrodes from the silicon chip for relocation onto a low-cost, disposable substrate. This enables reusability of the high-performance CMOS chip, at the same time providing a low-cost route for manufacture of the active thin-film electrodes using large-area processing. The use of disposable thin-film chip also enables customised designed electrodes for different applications, such as extra high sensitivity concentration sensors. In this work, DNA concentration measurements are performed, and it shows a doubling of sensitivity over the previously reported system.This work is partially supported by Isaac Newton Trust.This is the accepted manuscript of a paper published in Sensors and Actuators B (Ma H, Li J, Cheng X, Nathan A, Sensors and Actuators B 2015, 21, 77–82, doi:10.1016/j.snb.2015.01.044)

Miniaturization of fluorescence sensing in optofluidic devices

International audienceSuccessful development of a micro-total-analysis system (μTAS, lab-on-a-chip) is strictly related to the degree of miniaturization, integration, autonomy, sensitivity, selectivity, and repeatability of its detector. Fluorescence sensing is an optical detection method used for a large variety of biological and chemical assays, and its full integration within lab-on-a-chip devices remains a challenge. Important achievements were reported during the last few years, including improvements of previously reported methodologies, as well as new integration strategies. However, a universal paradigm remains elusive. This review considers achievements in the field of fluorescence sensing miniaturization, starting from off-chip approaches, representing miniaturized versions of their lab counter-parts, continuing gradually with strategies that aim to fully integrate fluorescence detection on-chip, and reporting the results around integration strategies based on optical-fiber-based designs,optical layer integrated designs, CMOS-based fluorescence sensing, and organic electronics. Further successful development in this field would enable the implementation of sensing networks in specific environments that, when coupled to Internet of-Things (IoT) and artificial intelligence (AI), could provide real-time data collection and, therefore, revolutionize fields like health, environmental, and industrial sensing

Microfluidics based DNA hybridization: mathematical modeling issues and future challenges

In this paper, various mathematical modeling strategies associated with the analysis of the kinetics and the transport processes pertinent to microfluidics-based DNA hybridization methodologies are critically reviewed. In particular, the coupling of specific/non- specific hybridization kinetics with the fluid flow, heat transfer and mass transfer equations is described in detail. Methodologies for obtaining faster DNA hybridization rates are also discussed and the corresponding mathematical modeling issues are identified to define the scope of ongoing and future research endeavours

Micromolar metabolite measurement in an electronically multiplexed format

The detection of metabolites such as choline in blood are important in clinical care for patients with cancer and cardiovascular disease. Choline is only present in human blood at low concentrations hence accurate measurement in an affordable point-of-care format is extremely challenging. Integration of microfluidics on to complementary metal-oxide semiconductor (CMOS) technology has the potential to enable advanced sensing technologies with extremely low limit of detection that are well suited to multiple clinical metabolite measurements. Although CMOS and microfluidics are individually mature technologies, their integration has presented challenges that we overcome in a novel, cost-effective, single-step process. To demonstrate the process, we present the microfluidic integration of a metabolomics-on-CMOS point-of-care platform with four capillary microfluidic channels on top of a CMOS optical sensor array. The fabricated device was characterised to verify the required structural profile, mechanical strength, optical spectra, and fluid flow. As a proof of concept, we used the device for the in-vitro quantification of choline in human blood plasma with a limit of detection of 3.2 M and a resolution of 1.6 M

An Outlook on Design Technologies for Future Integrated Systems

The economic and social demand for ubiquitous and multifaceted electronic systems-in combination with the unprecedented opportunities provided by the integration of various manufacturing technologies-is paving the way to a new class of heterogeneous integrated systems, with increased performance and connectedness and providing us with gateways to the living world. This paper surveys design requirements and solutions for heterogeneous systems and addresses design technologies for realizing them

Development of a microfluidic device for gaseous formaldehyde sensing = Développement d\u27un dispositif microfluidique pour la détection de formaldéhyde à l\u27état gazeux

Formaldehyd (HCHO) ist eine chemische Verbindung, die bei der Herstellung einer großen Zahl von Haushaltsprodukten verwendet wird.Charakteristisch ist seine hohe Flüchtigkeit aufgrund einer niedrigen Siedetemperatur ($T = - 19\ ℃$). Daher ist HCOH fast überall als Luftschadstoff in Innenräumen vorhanden. Die Miniaturisierung analytischer Systeme zu Handheld-Gerät hat das Potenzial, nicht nur effizientere, sondern auch empfindlichere Instrumente für die Echtzeitüberwachung dieses gefährlichen Luftschadstoffs zu ermöglichen. Die vorliegende Doktorarbeit präsentiert die Entwicklung eines Mikrofluidik-Geräts für die Erfassung von HCHO basierend auf der Hantzsch-Reaktion.Hierbei wurde der Schwerpunkt auf die Komponente für Fluoreszenzdetektion gelegt. Es wurde eine umfangreiche Literaturrecherche durchgeführt, die es erlaubt, den Stand der Technik auf dem Gebiet der Miniaturisierung des Fluoreszenzsensors zusammenzufassen. Auf Grund dieser Studie wurde ein modulares Fluoreszenzdetektionskonzept vorgeschlagen, das um einen CMOS-Bildsensor (CIS) herum entwickelt wurde. Zwei dreischichtige Fluidikzellenkonfigurationen (Konfiguration 1: Quarz - SU-8 3050 - Quarz und Konfiguration 2: Silizium - SU-8 3050 - Quarz) wurden in Betracht gezogen und parallel unter den gleichen experimentellen Bedingungen getestet. Die Verfahren der Mikrofabrikation der fluidischen Zellen wurden detailliert beschrieben, einschließlich des Integrationsprozesses der Standardkomponenten und der experimentellen Verfahren. Der CIS-basierte Fluoreszenzdetektor bewies seine Leistungsfähigkeit, eine anfängliche HCHO-Konzentration von 10 µg/L vollständig in 3,5-Diacetyl-1,4-dihydrolutidin (DDL- derivatisiert) sowohl für die Quarz- als auch für die Silizium-Fluidikzellen zu detektieren. Beide Systemewiesenein Abfragevolumen von 3,5 µL auf. Ein offensichtlich höheres Signal-Rausch-Verhältnis (SNR) wurde für die Silizium-Fluidzelle ($\text{SNR}_{\text{silicon}} = 6.1$) im Vergleich zur Quarz-Fluidzelle ($\text{SNR}_{\text{quartz}} = 4.9$) beobachtet. Die Verstärkung der Signalintensität in der Silizium-Fluidzelle ist wahrscheinlich auf den Silizium-Absorptionskoeffizienten bei der Anregungswellenlänge zurückzuführen,$a\left( \lambda_{\text{abs}} = 420\ nm \right) = 5 \bullet 10^{4}\text{cm}^{- 1}$. Dieser Koeffizient ist ungefähr fünfmal höher als der Absorptionskoeffizient bei der Fluoreszenzemissionswellenlänge $a\left(\lambda_{\text{em}} = 515\ nm \right) = 9.25 \bullet 10^{3}\text{cm}^{- 1}$. HCHO wird aufgrund seiner relativ hohen Konstanten für das Henry-Gesetz sehr schnell in ein flüssiges Reagenz aufgenommen. Somit hängt die Auswahl des molekularen Einfangverfahrens (Schwallströmung, Ringströmung oder membranbasierte Strömungswechselwirkung) von derLeistungsfähigkeit des Fluoreszenzdetektors ab. Ein vorläufiges Konzept, das auf der Verwendung einer Gas-Flüssigkeitsmembran-basierten Wechselwirkung zum ständigen Abfangen des gasförmigen HCHO basiert, wurde eingeführt. Hierzu wurden kompatible Materialien und Herstellungsmethoden identifiziert. Darüber hinaus wurden CFD-Simulationen durchgeführt, um die Mikrokanallänge unter verschiedenen hydrodynamischen Bedingungen abzuschätzen, die für eine vollständige HCHO-Derivatisierung erforderlich sind. Eine Verbesserung und Vereinfachung auf der Grundlage von sehrnempfindlichen Fluoreszenzdetektoren mit niedrigen Detektionsgrenzen könnte zukünftig basierend z. B. auf Schwallströmung oder Ringströmung möglich sein

Advanced microstructured platforms for neuroscience: from lab-on-chips for circadian clock studies to next generation bionic 3D brain tissue models

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian pacemaker which coordinates circadian rhythms in the central nervous system (CNS) and across the entire body. The SCN receives light input from the eyes through the retinohypothalamic tract and then it synchronizes other clocks in the CNS and periphery, thus orchestrating rhythms throughout the body. However, little is known about how so many cellular clocks within and across brain circuits can be effectively synchronized to entrain the coordinated expression of clock genes in cells distributed all over the brain. In this work I investigated the possible implication of two possible pathways: i) paracrine factors-mediated synchronization and ii) astrocytes-mediated synchronization. To study these pathways, I adopted an in vitro research model that I developed based on a lab-on-a-chip microfluidic device designed and realized in our laboratory. This device allows growing and compartmentalizing distinct neural populations connected through a network of astrocytes or through a cell-free channel in which the diffusion of paracrine factors is allowed. By taking advantage of this device, upon its validation, I synchronized neural clocks in one compartment and analyzed, in different experimental conditions, the induced expression of clock genes in a distant neural network grown in the second compartment. Results show that both pathways can be involved, but might have different roles. Neurons release factors that can diffuse to synchronize a neuronal population. The same factors can also synchronize astrocytes that, in turn, can transmit astrocyte-mediated molecular clocks to more distant neuronal populations. This is supported by experimental data obtained using microfluidic devices featuring different channel lengths. I found that paracrine factors-mediated synchronization occurs only in the case of a short distance between neuronal populations. On the contrary, interconnecting astrocytes define an active channel that can transfer molecular clocks to neural populations also at long distances. The study of possibly involved signaling factors indicate that paracrine factors-mediated synchronization occurs through GABA signaling, while astrocytes-mediated synchronization involves both GABA and glutamate. These findings strength the importance of the synergic regulation of clock genes among neurons and astrocytes, and identify a previously unknown role of astrocytes as active cells in distributing signals to regulate the expression of clock genes in the brain. Preliminary results also show a correlation between astrocyte reactivity and local alterations in neuronal synchronization, thus opening a new scenario for future studies in which disease-induced astrocyte reactivity might be linked to alterations in clock gene expression.Three-dimensional (3D) brain models hold great potential for the generation of functional in vitro models to advance studies on human brain development, diseases and possible therapies. The routine exploitation of such models, however, is hindered by the lack of technologies to chronically monitor the activity of neural aggregates in three dimensions. A promising new approach consists in growing bio-artificial 3D brain model systems with seamless tissue-integrated biosensing artificial microdevices. Such devices could provide a platform for in-tissue sensing of diverse biologically relevant parameters. To date there is very little information on how to control the extracellular integration of such microscale devices into neuronal 3D cell aggregates. In this direction, in the present work I contributed to investigated the growth of hybrid neurospheroids obtained by the aggregation of silicon sham microchips (100x100x50\u3bcm3) with primary cortical cells. Interestingly, by coating microchips with different adhesion-promoting molecules, we reveal that surface functionalization can tune the integration and final 3D location of self-standing microdevices into neurospheroids. Morphological and functional characterization suggests that the presence of an integrated microdevice does not alter spheroid growth, cellular composition, nor network activity and maturation. Finally, we also demonstrate the feasibility of separating cells and microchips from formed hybrid neurospheroids for further single-cell analysis, and quantifications confirm an unaltered ratio of neurons and glia. These results uncover the potential of surface-engineered self-standing microdevices to grow untethered three-dimensional brain-tissue models with inbuilt bioelectronic sensors at predefined sites

Scale up of advanced packaging and system integration for hybrid technologies

This paper presents an overview of challenges in system integration for 2.5D/3D assemblies, including copackaged optics and electronics, MEMS and microfluidics. It addresses the gap between early-stage prototypes and volume manufacturing that need true advanced packaging and system integration to realize their complex multi-technology devices. This is done by means of a virtual demonstrator that include both 2.5D/3D assemblies of ASICs and integrated photonic devices, as well as MEMS and microfluidics devices. It also addresses lowering the cost barrier for users accessing these technologies for their products, such that it will enable an increased uptake of system integration by the industry at large

Roadmap on semiconductor-cell biointerfaces.

This roadmap outlines the role semiconductor-based materials play in understanding the complex biophysical dynamics at multiple length scales, as well as the design and implementation of next-generation electronic, optoelectronic, and mechanical devices for biointerfaces. The roadmap emphasizes the advantages of semiconductor building blocks in interfacing, monitoring, and manipulating the activity of biological components, and discusses the possibility of using active semiconductor-cell interfaces for discovering new signaling processes in the biological world