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ECE 485 - Introduction to Microelectromechanical Devices and Systems

Extended Description of Syllabus Topics

Introduction to biosensors
Provide a broad overview of the field of biosensors, including a historical prospective of how biosensors have developed, and the applications of biosensors in the areas of pharmaceutical research, diagnostic testing, environmental detection, and others. We will define what constitutes a biosensor, and how specific applications result in different requirements for sensitivity, cost, size, and resolution for both the sensor element and the detection instrumentation. The introductory lectures will provide the context for the rest of the course and briefly introduce the concepts of selectivity, transducer phenomenology (acoustic, optical, electrochemical), and figures of merit.

Bioselective layers
Describe how biomolecular selectivity is conferred to biosensors through incorporation of proteins, DNA, peptides, and lipids onto membranes and transducer surfaces. Will give examples and compare physical adsorption, covalent attachment, and entrapment methods of ligand attachment, and discuss attachment methods that result in maintenance of immobilized ligand activity. Methods for application of bioselective layers in desired patterns will be described including pin-based spotting, ink-jet dispensing, and microstamp printing.

Biomolecular structure and function
A short review of protein and DNA biochemistry will be given. We will review the physical structure of the DNA molecule, and describe how the molecule may be linked to a biosensor surface or to a label. We will review the method through which DNA encodes protein, and the amino acids that proteins are composed of. We will describe protein folding, the formation of binding epitopes, and give examples of protein structures obtained through x-ray crystallography. The structure of antibody molecules will be described.

Mass transport
We will discuss how mass transport of analytes to the surface of the biosensor transducer can be used to limit or enhance the detected signal. The kinetics of diffusion-limited mass transport in stagnant systems will be described. The design of microfluid flow systems that interface with biosensors will also be covered. Different assay types (displacement, competitive, sandwich, and direct) will be described.

Electrochemistry
The fundamental concepts behind Galvanic (electroanalytical) methods will be described, including the Nernst equation, the use of reference electrodes, the selection of ion selective electrodes, and the use of mediators. We will consider the types of analytes that are detectable by electrochemistry, including dissolved oxygen and hydrogen peroxide. Several transducer designs will be described and compared.

Homogeneous and heterogeneous assays
Describe the differences, advantages, and limitations of biosensors designed to detect homogeneous and heterogeneous biochemical interactions. Introduce the concept of solution-based biosensor micro/nanoparticles and briefly give examples of this type of transducer.

Figures of merit
Mathematically define sensitivity, resolution, selectivity, dynamic range, and noise in the context of biosensors. Describe sources of measurement error such as sensor drift, thermal drift, spatial uniformity, and manufacturing repeatability and how they affect performance figures of merit. Discuss the use of reference sensors to correct common mode error sources. Discuss aspects of transducer and instrumentation design that impact the figures of merit.

Clark electrode for glucose sensing
The operation of the classical Clark electrochemical sensor for glucose will be described in detail, and improvements in the basic design that have evolved over time will be covered. We will describe the operation of modern blood glucose sensors for diabetes monitoring.

Acoustic wave
Sensors based upon the principle of acoustic resonator frequency modulation will be described, in particular the quartz crystal microbalance governed by the Sauerbrey equation. Examples of detection will be provided, and we will discuss the advantages and drawbacks of acoustic-based sensors.

Surface plasmons
The phenomenon of surface plasmons in metal films will be described, and we will discuss how the effect is used to detect biomolecules. The optical properties of biological materials will be covered. Various methods for coupling light to surface plasmons and collecting a signal will be covered, including the Kreitchmann configuration for prism coupleing, grating coupled SPR, and imaging SPR. The advantages and drawbacks of SPR will be discussed.

Optical biosensors
Sensors based on the use of optical waveguides and evanescent fields will be described. The design of early fiber optic and slab waveguide sensors will be described, as well as methods that have been used to improve sensitivity and resolution through the use of interference, multiple optical modes, and integrated reference devices.

Fluorescence
The principles behind chemical fluorophores will be covered, including the most common fluorescent labels used for DNA and proteins. Methods for fluorophore excitation and visualization will be covered including the fluorescent microscope and the fluorescent microarray scanner. We will describe how fluorophores can be used to visualize molecules, and limitations such as epitope blocking and quenching that limit their functionality.

Nanoparticle labels
Alternate means for providing fluorescent visualization will be described including quantum dots, carbon nanotubes, and metal nanoparticles. The use of such labels for homogeneous assays, including particle functionalization and readout will be described.

Avidin-biotin mediated biosensors
We will return to the topic of surface chemistry in more depth, using the avidin-biotin system as a highly popular example of how many proteins and DNA molecules can be covalently linked to a transducer surface.

Transducer functionalization methods
We will go beyond the avidin-biotin system to describe alternate means for chemical functionalization of biosensors and attachment of active ligands. Bifunctional linkers, self-assembled monolayers, and hydrogel methods will be described. Nonspecific binding and methods for blocking nonspecific analytes will be discussed.

DNA microarray
Methods for hybridization of DNA to a surface, and detection of fluorescent-tagged DNA in an analyte solution will be described. Method for comparison/reference analysis using multiple color tags will be discussed, as will application to gene identification and gene sequencing.

Fluorescent beads and particles
The use of functionalized fluorescent beads (Luminex) and metal nanoparticle conjugates (Nanosphere) to perform protein-protein binding assays and to identify the presence of protein in a test sample will be described.

Photonic crystal biosensors
A photonic crystal-based optical biosensor manufactured and used in the field of pharmaceutical discovery (SRU Biosystems) will be described.

Total internal reflection fluorescence (TIRF)
Combination of optical waveguides or evanescent fields with fluorophores provides a means for amplifying the output of fluorophores and increasing signal-to-noise ratio. We will describe the design and use of TIRF devices for increasing the sensivity of heterogeneous fluorescent assays.

Class Project
Students will select a biosensor from a list alternatives generated by the instructor. Students are responsible for finding reference material on the sensor, and performing an analysis of the advantages and disadvantages relative to one of the sensor transducers presented in class. Students will be allowed to work in groups of 2-3. The group will be responsible for preparing and presenting a 15 minute lecture to the class that describes their analysis. The lecture must contain a concise explanation of the sensor phenomenon, and a quantitative analysis of sensitivity, resolution and other relevant performance metrics. Consideration will be given to the amount of thought put into the presentation, particularly in the areas of instrumentation complexity, manufacturing complexity, and methods for improving the sensor.

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