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Introduction to BioMEMS & Medical Microdevices

Micro Total Analysis Systems (µTAS)
Companion lecture to the textbook: Fundamentals of BioMEMS and Medical Microdevices,
by Dr. Steven S. Saliterman,

Micro Total Analysis (µTAS)

Lab-on-a-Chip (LOC)
Protein LOC
Other LOC

Steven S. Saliterman, MD, FACP

Protein Chips
DNA Chips

Protein Microarrays
DNA Microarrays
Other Microarrays

Design Opportunities
Chain of operations on a single chip
Hybrids of multiple chips

Power sources

Sample throughput

Micro Total Analysis Systems (µTAS)


Integrated detectors
Integrated electrodes

Steven S. Saliterman, MD, FACP

User interface

Chain of Operations Steven S. MD. Saliterman. FACP Li 2004 .

FACP Image courtesy of Micronit .Micromixers z Example of a mixer chip: Steven S. MD. Saliterman.

MD.z Micromixer design considerations: Viscosity of liquids. z Steven S. Saliterman. width and length. FACP Micronit . including depth. z The dimensions of the channels. z Total volume and flow rate of the channel(s). z The dimensions of the chip to allow easy analysis.

FACP Image courtesy of Micronit .Microchemical Reactors z Examples of chemical reactor chips: Steven S. MD. Saliterman.

The desired pressure. The desired temperature. The dimensions of the chip to allow easy analysis. MD. Total volume and flow rate of the channel(s). The dimensions of the channels. including depth. Saliterman. The desired reaction time. width and length.z Reactor z z z z z z z design considerations: Viscosity of the liquids. Steven S. FACP Micronit .

FACP Image courtesy of Micronit . Saliterman. MD.Detection z Examples of integrated electrodes: Steven S.

Saliterman.below 400 nm used fused silica (quartz) Laser: z Refraction of light is a common detection method. Steven S. z Platinum is usually used (also gold. copper) z z Fluorescence: z z Consider the wavelength of emission. FACP . MD.z Detection z strategies: Electrodes for electrochemical detection: Metal layers be incorporated.

FACP Image courtesy of Micronit .Interconnectivity z Examples of chip holders: Steven S. Saliterman. MD.

microscope access). FACP . z Material (PEEK and stainless steel are used). Saliterman. z Size of chip capillaries.z Interconnection specifications include: Number of ports. z Steven S. z Method of detection (eg. z Pressure and temperature operating range. MD.

Glass. molecule and particle handling: z z Mechanical. silicon and polymers. FACP . MD. Surface modification: z z z Linear and radial arrays. latex agglutination test. Steven S. drug delivery. semipermeable membranes. optical. Saliterman. chemical. Microspheres: z Bioseparations. hydrogels. Immobilization strategies. electrokinetic.Techniques z Capillary array electrophoresis: z z Cell.

Capillary Electrophoresis Steven S. 2004 and Image courtesy of Micronit . FACP Guber et al. MD. Saliterman.

MD. Saliterman. FACP Blazej and et al. 2003 .Linear to Radial CE Arrays Steven S.

MD. Saliterman. FACP .Cell. Molecular and Particle Handling z Mechanical z Impedance Counting and Sizing z Semipermeable Membranes z Dielectrophoresis z Protein Adhesive Rolling z Optical Tweezers and Scissors z Hydrogels Steven S.

2003 . MD. Saliterman. and et al. W.Mechanical z A filter chamber fabricated by DRIE in a silicon substrate: Steven S. FACP van der Wijngaart.

Saliterman. FACP . MD.Impedance Cell Sizing Steven S.

FACP .Semipermeable Membranes z Permselective membranes for cell immunoisolation: z z z z High density uniform pores allow sufficient permeability to nutrients and hormones while preventing the passage of immunoglobulins. Saliterman. Steven S. For example islet-cell transplantation. Uniform pores can be micromachining in silicon. MD. Polyethylene terephthalate (PET) membranes may be machined with an excimer laser to produce pores as sieves.

Steven S. separation. Potential uses include: z z z Isolation and detection of cancer cells.Dielectrophoresis z z Physical phenomenon whereby dielectric particles. trapping and positioning of cells in dilute suspensions. in response to a spatially nonuniform electric field. experience a net force directed toward locations with increasing or decreasing field intensity according to the physical properties of the particles and medium. in threedimensional structures to handle and characterize adherently growing cells. Concentration. including their adhesion. surface migration and cultivation. Saliterman. MD. FACP . Strong electric fields have been used by Fuhr et al.

MD. School of Electronic Engineering. FACP IBMM. Saliterman. Bangor University .Particles in a Non-Uniform Electric Field Steven S.

Optical Tweezers and Scissors z Laser tweezers: Steven S. MD. Saliterman. FACP Munce 2005 .

Principle of Operation Steven S. Saliterman. MD. FACP Odde and Renn 2000 .

FACP Odde and Renn 2000 . MD.Applications Steven S. Saliterman.

Hydrogels z Hybrid check valve: Steven S. FACP Bauer and Beebe 2003 . Saliterman. MD.

MD.z Temperature sensitive tethered hydrogel valves: Steven S. FACP Ziaie et al. Saliterman. 2004 .

z Isolation the hydrogel from the main fluid flow: Steven S. FACP Bauer and Beebe 2003 . Saliterman. MD.

Surface Modification z z z z Chemical surface modification may enhance electrokinetic effects and create areas of hydrophobicity. FACP . MD. Protein or cell-resistant surfaces are a requirement for medical devices that contact biological fluids. Steven S. Immobilization strategies for controlling fluids and positioning analytes for reactions and detection commonly involve some form of surface modification. Saliterman. hydrophilicity and adhesion that assist in fluid handling. Biological surface science is the study of properties and processes at interfaces between synthetic materials and biological environments and fabrication of biofunctional surfaces.

PMMA) are hydrophobic. Saliterman. MD. FACP . Electro-deposited silver may increase hydrophobicity allowing control of flow. and are hydrophilic. To control EOF. Steven S.Hydrophilicity and Hydrophobicity z Silicon dioxide surfaces (and glass) are negatively charged at neutral pH due to deprotonated silanol groups. z z z z z An EDL will form when in contact with an electrolyte solution. both the sign of the surface charge and its distribution on the surface are important. Polymers (eg. Discrete areas of positive charge can be achieved by patterning with positively charged poly(allylamine hydrochloride) (PAH).

IgG and albumin bind to sensors and other surfaces. MD. non-immunogenic and non-antigenic polymer may prevent these phenomena. Saliterman.Selective Protein Adsorption z z z Biofouling occurs as platelets. Poly(ethylene glycol) (PEG): z z A nontoxic. Stable. fibrinogen. UV-induced graft polymerizations. non-fouling surfaces may be created by: z z z Chemical coupling reactions. Self assembled monolayers (SAMs). Steven S. FACP . Foreign body giant cells (FBGC) may envelope surfaces in response to macrophages being drawn to areas of inflammation.

MD. 2005 . FACP Lan et al.PEG and Gold Surface Modification Steven S. Saliterman.

z Steven S. z Non-specific adsorption of analytes. Saliterman. z Surface bond chemical moieties. z Hydrophobicity (plastics tend to be negatively charged).Polymer Substrates z Attributes: Machinability. z Zeta-potential and associated electroosmosis flow mobility (ratio of flow rate to electric field). MD. FACP . z Solvent resistance.

H2O. N2. Reactions with pendent groups typically occur. biocompatibility and permeability. H2. UV and plasma (Ar. NO2 and F2). Ne. CO2. MD. Saliterman. Non-Covalent Modification z Protein and other surfactant coatings. CO. NH2. O2. surface charge density. May enhance hydrophilicity. hydrophobicity. He. adhesion. Steven S. FACP .Techniques z Covalent chemical modification: z z z Energetic surface treatments: z z z Surfaces retain chemical integrity over an extended period of time compared to non-covalent modification.

peptides. Saliterman. FACP . Laser tweezers. Lipid bilayers offer efficient reduction of nonspecific cell and protein binding. Step modification of a substrate surface by first immobilizing proteins. or carbohydrates as a means to promote cell attachment. Surface modification: z z z z z Hydrophilicy and hydrophobicity as discussed. Biospecific reactions such as with biotinstreptavidin. Hydrogel matrices. Steven S. MD.Immobilization Strategies z z z Mechanical barriers and traps.

latex diagnostics. and vascular occluders. MD. Microspheres of submicron diameter are sometimes referred to as nanoparticles or nanospheres. Saliterman. drug and enzyme carriers. “Polymer colloid” (sometimes referred to as “latex”) refers to a suspension or dispersion of polymeric microspheres having a diameter in the order of sub-micron to several microns. affinity bioseparators.Microspheres z z z Applications include use as absorbents. Steven S. FACP .

FACP Images courtesy of BioSphere Medical .Therapeutic Microspheres Embospheres Round PVA PVA Targeted occlusion of blood vessels feeding a hypervascularized tumor or arteriovenous malformation. MD. Saliterman. Microspheres are compressible and hydrophilic Steven S.

hydrogels. Saliterman. FACP . Microspheres: z Bioseparations. and offer several design opportunities. chemical. Steven S. molecule and particle handling: z z Mechanical. semipermeable membranes. drug delivery. Immobilization strategies. electrokinetic. Capillary array electrophoresis: z z Cell. optical. Glass. Surface modification: z z z Linear and radial arrays. latex agglutination test. silicon and polymers. MD.Summary z z Micro Total Analysis Systems include lab-on-a-chip and microarray devices.