A Micro Total Analysis Systems

8/9/2019 A Micro Total Analysis Systems

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Introduction to BioMEMS & Medical Microdevices

Micro Total A nalys is Sys tem s (µTAS)Companion lecture to the textbook: Fundamentals of BioMEMS and Medical Microdevices,

by Dr. Steven S. Saliterman, www.tc.umn.edu/~drsteve


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Steven S. Salit erman, MD, FACP

Microanalysis

BiochipsLab-on-a-Chip (LOC) Microarrays

DNA Microarrays

Protein Microarrays

Micro Total Analysis (µTAS)

Microanalysis

Other Microarrays

DNA LOC

Protein LOC

Other LOC

Protein Chips

DNA Chips


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Design Opportunities

Micro Total Analysis Systems (µTAS)

Chain of operations on a single chip

Hybrids of multiple chips

Interconnectivity

Integrated electrodes

Integrated detectors

User interfacePower sources

Sample throughput


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Chain of Operations

Li 2004


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Example of a mixer chip:

Image courtesy of Micronit

Micromixers


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Micromixer design considerations:Viscosity of liquids,The dimensions of the chip to allow easyanalysis,The dimensions of the channels, includingdepth, width and length,

Total volume and flow rate of thechannel(s).

Micronit


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Examples of chemical reactor chips:


Microchemical Reactors


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Examples of integrated electrodes:


Detection


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Detection strategies:Electrodes for electrochemical detection:

Metal layers be incorporated,Platinum is usually used (also gold, copper)

Fluorescence:Consider the wavelength of emission- below 400nm used fused silica (quartz)

Laser:Refraction of light is a common detectionmethod.


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InterconnectivityExamples of chip holders:



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Interconnection specifications include:Number of ports,Pressure and temperature operating range,Material (PEEK and stainless steel areused),Size of chip capillaries,

Method of detection (eg. microscopeaccess).


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TechniquesCapillary array electrophoresis :

Linear and radial arrays.Cell, molecule and particle handling :Mechanical, semipermeable membranes,electrokinetic, chemical, optical, hydrogels.

Surface modification :Glass, silicon and polymers,Immobilization strategies.

Microspheres :Bioseparations, latex agglutination test, drugdelivery.


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Capillary Electrophoresis

Guber et al. 2004 and Image courtesy of Micronit


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Linear to Radial CE Arrays

Blazej and et al. 2003


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Cell, Molecular and Particle Handling

MechanicalImpedance Counting and SizingSemipermeable Membranes

DielectrophoresisProtein Adhesive RollingOptical Tweezers and ScissorsHydrogels


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Mechanical A filter chamber fabricated by DRIE in a siliconsubstrate:

van der Wijngaart, W. and et al. 2003


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Impedance Cell Sizing


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Semipermeable Membranes

Permselective membranes for cell

immunoisolation:High density uniform pores allow sufficientpermeability to nutrients and hormones whilepreventing the passage of immunoglobulins.

For example islet-cell transplantation.Uniform pores can be micromachining insilicon.

Polyethylene terephthalate (PET) membranesmay be machined with an excimer laser toproduce pores as sieves.


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Dielectrophoresis

Physical phenomenon whereby dielectric particles, inresponse to a spatially nonuniform electric field ,experience a net force directed toward locations withincreasing or decreasing field intensity according tothe physical properties of the particles and medium .Potential uses include:

Isolation and detection of cancer cells.Concentration, separation, trapping and positioning of cells indilute suspensions.Strong electric fields have been used by Fuhr et al. in three-dimensional structures to handle and characterize adherentlygrowing cells, including their adhesion, surface migration andcultivation.


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Particles in a Non-Uniform Electric Field

IBMM, Schoo l of Electronic Engineering,Bangor University


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Optical Tweezers and Scissors

Laser tweezers:

Munce 2005


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Principle of Operation

Odde and Renn 2000


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Applications

Odde and Renn 2000


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Hydrogels

Hybrid check valve:

Bauer and Beebe 2003


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Temperature sensitive tethered hydrogel

valves:

Ziaie et al. 2004


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Isolation the hydrogel from the main fluid flow:

Bauer and Beebe 2003


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Surface Modification

Chemical surface modification may enhanceelectrokinetic effects and create areas ofhydrophobicity, hydrophilicity and adhesion that assistin fluid handling.Biological surface science is the study of propertiesand processes at interfaces between syntheticmaterials and biological environments and fabricationof biofunctional surfaces.Protein or cell-resistant surfaces are a requirement formedical devices that contact biological fluids.Immobilization strategies for controlling fluids andpositioning analytes for reactions and detectioncommonly involve some form of surface modification.


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Hydrophilicity and Hydrophobicity

Silicon dioxide surfaces (and glass ) are negativelycharged at neutral pH due to deprotonated silanolgroups, and are hydrophilic .

An EDL will form when in contact with an electrolytesolution.To control EOF, both the sign of the surface charge andits distribution on the surface are important.Discrete areas of positive charge can be achieved bypatterning with positively charged poly(allylaminehydrochloride) (PAH).Electro-deposited silver may increase hydrophobicityallowing control of flow.

Polymers (eg. PMMA) are hydrophobic .


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Selective Protein Adsorption

Biofouling occurs as platelets, fibrinogen, IgG

and albumin bind to sensors and other surfaces.Foreign body giant cells (FBGC) may envelopesurfaces in response to macrophages beingdrawn to areas of inflammation.Poly(ethylene glycol) (PEG):

A nontoxic, non-immunogenic and non-antigenicpolymer may prevent these phenomena.

Stable, non-fouling surfaces may be created by:Chemical coupling reactions,UV-induced graft polymerizations,Self assembled monolayers (SAMs).


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PEG and Gold Surface Modification

Lan et al. 2005


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Polymer Substrates

Attributes:

Machinability,Solvent resistance,Hydrophobicity (plastics tend to be

negatively charged),Zeta-potential and associatedelectroosmosis flow mobility (ratio of flow

rate to electric field),Surface bond chemical moieties,Non-specific adsorption of analytes.


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Techniques

Covalent chemical modification:Surfaces retain chemical integrity over an extendedperiod of time compared to non-covalentmodification.Reactions with pendent groups typically occur.

Energetic surface treatments:UV and plasma (Ar, Ne, He, H 2, NH 2, CO, CO 2, O 2,H2O, N 2, NO 2 and F 2),May enhance hydrophilicity, hydrophobicity,adhesion, surface charge density, biocompatibilityand permeability.

Non-Covalent ModificationProtein and other surfactant coatings.


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Immobilization Strategies

Mechanical barriers and traps.

Laser tweezers.Surface modification:Hydrophilicy and hydrophobicity as discussed.Lipid bilayers offer efficient reduction of nonspecificcell and protein binding.Biospecific reactions such as with biotin-streptavidin.Step modification of a substrate surface by first

immobilizing proteins, peptides, or carbohydratesas a means to promote cell attachment.Hydrogel matrices.


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Microspheres

Applications include use as absorbents, latex

diagnostics, affinity bioseparators, drug andenzyme carriers, and vascular occluders.“Polymer colloid” (sometimes referred to as“latex” ) refers to a suspension or dispersion ofpolymeric microspheres having a diameter inthe order of sub-micron to several microns.Microspheres of submicron diameter are

sometimes referred to as nanoparticles ornanospheres .


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Therapeutic Microspheres

Images courtesy of B ioSphere Medical

Embospheres Round PVA PVA

Microspheres are compressible and hydrophilic

Targeted occlusion ofblood vessels feeding a

hypervascularized tumoror arteriovenousmalformation.


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Summary

Micro Total Analysis Systems include lab-on-a-chipand microarray devices, and offer several designopportunities.Capillary array electrophoresis :

Linear and radial arrays.Cell, molecule and particle handling :

Mechanical, semipermeable membranes, electrokinetic,chemical, optical, hydrogels.Surface modification :

Glass, silicon and polymers,Immobilization strategies.

Microspheres :Bioseparations, latex agglutination test, drug delivery.

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A Micro Total Analysis Systems