• Blended Learning & Flipped Classroom
• MOOC

Goals

The objective of the course is to present to the students, approaching the end of their M.Sc. educational carrier, an overview of the field of biochips and analytical lab-on-chip microsystems (whose recent advances are relevant both from the scientific and industrial point of view) with specific insights on the technological aspects of the interface between (micro)electronics and electrochemistry and biology, both at cellular and molecular levels. The content of the course reflects the multidisciplinarity of the nano-bio-tech field and is mainly focused on the different manipulation and detection approaches of biochemical target analytes on chip. The main goal is to provide the students with the fundamental theoretical tools for the design of active microfluidic systems (basics of fluid dynamics at the microscale), and of the engineering of the detection systems (optical and electrochemical transducers). At the same time, several practical examples are discussed in order to illustrate design choices and trade-offs. Starting from 2020, a part of the course will be taught by means of innovative learning techniques. The topics of microfabrication (hard and soft-lithography) will be addressed by means of MOOC videos recorded in actual clean-rooms and fabrication facilities. Finally, a "blended" and "flipped-classroom" approach will be adopted in the last part of the course including a laboratory activity where student will fabricate real devices: at first they will be gropued in small teams (3-4 persons max.), will design at home the layout of the microchannels according to some design challenges posed by the teacher, and then will fabricate them in the lab with PDMS elastomer by means of replica molding. A characterization with colored fluids, digital microscopes and pumps will conclude this experimental activity.

Expected Learning Outcomes

Knowledge and understanding (Dublin Descriptor #1)

At the end of the course the students are expected to:

·         possess a good understanding of lab-on-chip systems (needs, applications, advantages and limits) and bio-electronics convergence

·         possess a basic knowledge of hard and soft lithographic microfabrication approaches

·         possess a basic knowledge of the laws describing the flow of liquid in microchannels and the forces to actuate particles in liquid

·         presses a good knowledge of the electrochemical interface and instrumentation for biosensing

·         possess a good knowledge of the DNA macromolecule and the instrumentation for its analysis

·         understand the potentials and challenges of CMOS/biochips integration

Applying knowledge and understanding (Dublin Descriptor #2)

At the end of the course the students are expected to:

·         be able to analyze and design a microfluidic system in laminar regime (fluidic sizing, choice of components such as pumps/valves), starting from the sample preparation and manipulation

·         be able to design an analytical assay (for instance for molecular recognition or DNA analysis)

·         be able to design integrated detectors (both optical and electrochemical)

·         be able to design current and impedance sensing circuits for biochips

Making judgements (Dublin Descriptor #3)

Students will be able to:

·         evaluate the most appropriate approach (materials, fabrication) to address an analytical need

·         apply the knowledge to different application areas

·         apply the knowledge to design a novel micro-device

Communication (Dublin Descriptor #4)

During the work in teams for the experimental laboratory, students will be able to communicate among each other (in the first phase at home, when the microfluidic channels are designed upon technological specifications set in the classroom). Then, during the lab. and the oral exam their communication skills are deployed to motivate their design choices and comment the experimental results.

Topics

The course is articulated in theoretical lessons, combined with quantitative exercises and with case studies oriented to the analysis and design of microsystems. An experimental laboratory consisting of: a design phase at home in teams with a propor design software and two days of experimental activity in the lab. (fabrication and characterization of a PDMS microfluidic device). Experts in the biochip field are also invited during the course to lecture seminars on specific topics, such as micromagnetism and DNA analysis, or to present the point of view of companies carrying on R&D in the biochip field (STMicroelectronics, Flextronics, Dianax etc…). A visit to the renewed clean-room and microfabrication facility of Politecnico di Milano (PoliFab) concludes the course.

1. Introduction to biochips: architecture of lab-a-chip micro-analytical systems, motivations and impact, design paradigms, market projections, basic biological macromolecules used for as receptors in affinity biosensors.

2. Introduction to microfluidics: fluid dynamics, Reynolds number, electrical equivalent of hydraulic circuits (fluidic capacitance) and electro-osmotic flow. Actuation forces for particle manipulation within biochips: diffusion, electrophoresis, dielectrophoresis, electrowetting and droplet-based digital microfluidics. Active and passive microfluidic components: valves, mixers and pumps.

3. Introduction to microfabrication: review of Silicon CMOS-MEMS processes, lithography, thin film deposition and patterning, as compared to elastomer (PDMS) and plastic based soft lithography (replica molding).

4. Optical detection: fluorescence (strengths and limitations, Atomic Force Microscopy), source-filter-detector architectures, integrated photonics for biosensing based on evanescent field (waveguides, Mach-Zehnder interferometers, ring resonators and contactless light monitors). Electrochemical detection: the electrochemical interface with physiological ionic solutions (charge transfer and induction).

5. Electrochemical instrumentation: analytical techniques (cyclic voltammetry, amperometry and impedance spectroscopy) and the potentiostatic workstations. Micro and nano-scale electrochemistry: effects of electrode scaling.

6. Low-noise current measurements: review of noise in electronic devices, the transimpedance amplifier (working principle, properties and limitations) and advanced circuit topologies (integrator-differentiator schemes with different CMOS-compatible bias resetting solutions).

7. Impedance measurements and instrumentation, comparison of sensing configurations: bridge, ratiometric, current sensing, lock-in detection, resonant circuits, FFT-based and time-domain approaches.

8. Detection of DNA: structure and properties, microarrays (spotting and probe synthesis), electrophoresis, amplification with Polymerase Chain Reaction and quantitative detection with real-time PCR and approaches for sequencing.

9. Biochips for molecular detection: resonating cantilevers for molecular weighing, amperometric detection of neurotransmitters, redox cycling, glucose sensors based on enzymatic mediators, and nanopores. Biochips for cellular detection: interface with electrogenic cells, equivalent model of passive cells, label-free impedance monitoring a cell colony dynamics and single cell counting and sizing with microfluidic impedance flow cytometry (design case study).

10. Sample preparation (cell lysis, sample mixing, concentration and purification). Microelectronics CMOS biochips: state of the art performance in CMOS detection, design criteria, advantages and limits, the critical role of the substrate, packaging and interfacing issues.

Basic prerequisites:

• fundamentals of Chemistry (ions, chemical bonds, redox reactions)
• fundamental of Physics (electric charge, electric and magnetic field, dielectrics)
• fundamental of Electronics (Ohm’s and Kickoff’s laws, operational amplifier, feedback circuit, impedance, Bode plots)

Assessment

Exams are held at the end of the course (no intermediate tests). The exam consists of a written test (of a duration of 2 hours) followed by an oral exam. The written test (assessing Dublin Descriptors 1 and 2) encompasses the solution of numerical exercises focusing on 2 types. The first type concerns the microfabrication and the fluidics (and components) of micro-channels and devices. The second type mostly focuses on electrochemical detection. The students will be asked to analyze circuits and systems, as well as to design them.

The outcome of the written tests is communicated to the students by email. Then, a meeting in the classroom is scheduled for the students to vision and discuss the correction of the written test. They can accept or refuse the evaluation, either by email or in-person communication. They can undertake the oral test in the following days, by agreeing a calendar with the teacher.

The oral discussion (assessing Dublin Descriptors 1,2,3,4) is mandatory for students achieving top marks in the ranking (> 27/30) in the written test and it is optional and open for all students with a mark above 17/30 in the written test. In the oral test (lasting 15 to 40 minutes) students will be asked discuss the ultimate limits of the different technologies, pros and cons, compare them, and to design complete systems to address novel design cases proposed during the oral exam.