Goal:

The objective of the course is to present to the students, approaching the end of their 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. 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.

Detailed program:

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.

Experimental laboratories:

Design, realization and characterization of microfluidic devices.

Expected learning results:

At the end of the course the student is expect to:

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

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

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

_ possess a good knowledge of hard and soft lithographic microfabrication approaches

_ be able to design integrated detectors (optical and electrochemical)

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

_ understand the potentials and challenges of CMOS/Biochips integration

The course is articulated in theoretical lessons, combined with quantitative exercises and with case studies oriented to the analysis and design of microsystems. 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, etc…). A visit to the renewed clean-room and microfabrication facility of Politecnico di Milano (PoliFab) concludes the course. Exams are held at the end of the course (no intermediate tests). The exam consists of a written test (2 hours) followed by an optional oral exam (which is mandatory for marks above 27).