bio-mems devices 1) drug to cell (or body), 2) cell to drug€¦ · the “smart pill” •...
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Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
BIO-MEMS DEVICES
1) DRUG TO CELL (OR BODY), 2) CELL TO DRUG
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Current Technology for Drug Delivery
• Include hypodermic needles, pills, and passive transdermalmethods
• Disadvantages:– Highly Invasive– Poor Control– Can be Ineffective
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Drug Delivery by MEMS
• Advantages– Improved Control– More Effective– Less Intrusive
• Disadvantages– Biocompatibility Concerns– Biofouling Issues
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Areas of Research
• In Vivo Devices– Within the body– Implanted or Ingested
• Transdermal Devices– Acts through the skin
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Reservoir Devices
• Passive– Pourous material allows
diffusion– Deteriorating membranes
• Active– Electrically activated
Biocompatibilty Issues:• Toxicity and damage to tissue• Functionality (Biofouling)
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Passive vs. Active
• Passive– Simpler to manufacture– No power source needed– Less control
• Active– More complex fabrication– Battery required– More biocompatibility
concerns– Much more control– Several means to stimulate
actuation
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
The “Smart Pill”
• Built-in sensor to detect when the drug is required• Artificial muscle membrane to release the drug
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Advantage of Implantable Drug Delivery
• Conventional drug delivery such as injection or pills
• Much farther from the ideal concentration over the time cycle
• MEMS implantable drug delivery systems
• Maintains a dosage level very close to the target rate
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Transdermal Devices
• Currently available:– Passive
• Can be ineffective and difficult to control• Improvements:
– Iontophoresis– Chemical Enhancers– Ultrasound
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Microneedles
• Microneedles are used to improve transdermal drug delivery
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Best DeviceMicroCHIPS Inc. Implantable Device
http://www.bu.edu/mfg/programs/outreach/etseminars/2002may/documents/santini.pdf
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Best Device
MicroCHIPS Inc. Implantable Device
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Why?
• Many different configurations make it quite versatile• Easy to implement• Simple yet effective• Smaller in size than the “Smart Pill”
http://www.itnes.com/pages/batteries.html
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Start with silicon waferapproximately 300 microns thickPECVD 300 nm thick siliconnitride
Silicon nitride patterned with photolithography and RIE etched
KOH anisotropic etch (silicon nitride acts as a mask and stop)
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Deposit gold cathode and anode membrane
PECVD silicon dioxide used as a dielectric
Patterned using PR and etched with RIE
Etched to gold membrane using RIE
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Invert and inject drug into reservoir using inkjet technology
Reservoirs capped with silicon nitride
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Actuation
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Steps following fabrication
• Integrated Circuitry manufactured• Combined with delivery chip and thin film battery into a
compact package
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Thin Film Battery
• No toxic materials used• Nothing to leak into the body• Can be recharged many times• 1.5 to 4.5 volts• Size:
– 0.5 to 25 cm2
– 15 microns thick
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Battery Cross Section
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Oxidation Reduction Reaction
• Au + 4Cl- [AuCl4]- + 3e-
• Au + mH2O [Au(H2O)m]3+ + 3e-
• 2Au + 3H2O Au2O3 + 6H+ + 6e-
• 2Cl- Cl2 +2e-
• Au2O3 + 8Cl- + 6H+ 2[AuCl4]- +3H2O
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Oxidation (corrosion) of Gold Reservoir Caps
• A stimulus voltage is applied for 10-50 μs to start the oxidation reaction
• Gold corrodes and goes into the body as harmless [AuCl4]-
http://www.njnano.org/pasi/event/talks/cima.pdf
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Gold Reservoir Cap
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Developing Technology
• Nano-channel Device
• Porous Hollow Silica Nanoparticles (PHSNP)• Quantum Dots
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Nano-channel Device
• Nano-channel filter• Simpler than
previous devices• Standard/Mass
production• Dimensions
optimized for strength
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Top of Base Substrate
• Drug enters entry flow chamber from entry port of top substrate
• Enters input fingers, passes through nano-channels
• Exits through output fingers and exit flow chamber
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Glucose Release
• Solution to constant drug delivery need
• Drawback: drugs pass through nano-channels at different rates – electrical integration and control of flow through nano-channels
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Porous Hollow Silica Nanoparticles (PHSNP)• Used in many different
applications
• Past drug carriers primarily oil-in-water units, liposomes, and nanoparticles and microparticles made of synthetic polymers and or natural macromolecules
• PHSNP diameter = 60-70nm, wall thickness = 10nm
• Synthesis of PHSNP involves CaCO3 template
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
PHSNP to carry Cefradine
• Treat bacterial infection by destroying cell walls
• Used for infection in airways, kidneys, post-surgery, other
Molecular structure of cefradine.
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Distribution of Cefradine in PHSNP
Distribution of pore diameters in the wall of PHSNP (a) before entrapping cefradine; (b) after entrapping cefradine.
Preparation process of drug carrier from PHSNP. (a) PHSNP; (b) suspension of cefradine and PHSNP; (c) PHSNP entrapped with cefradine.
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Release of Cefradine
• Stage one: 76% release in 20 min. – surface of PHSNP
• Stage two: 76%-82% release in 10 hours– pores of PHSNP
• Stage three: insignificant release from PHSNP hollow center
• Gradual release over time can be exploited in drug delivery applications
In vitro release profile of cefradine from PHSNP
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Quantum Dots
• Crystals containing a group of electrons – usually made of II-VI semiconductor cadmium selenide
• Nanometers wide, demonstrate quantum properties of single atoms, absorb and emit specific wavelengths of light
• Bind Taxol, a cancer-fighting drug, and a molecule with affinity to folic acid receptors to quantum dots, also effective when bound with antibodies
• Cancer cells have high concentration of folic acid receptors andcan be targeted
• Once excited with IR light, the bond is broken with the drug, Taxol, which is able to attack the cancerous cell
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
IR Illuminated Rat
• Implanted with tumor• Injected with quantum dots,
bound with Taxol• High concentration around tumor• Technique not as effective in
humans due to deep internal organs
• May be effective for skin and breast cancer
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
• Planar monitoring system
• Neurons cage array
• Living chips with peptide amphiphiles gels
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Jenker, Müller, Fromherz, Biol. Cybern. 84, 239-249 (2001)
•Simple
•Rugged
•Easiest solution
“Future hybrid neuron-semiconductor chips will consist of complex neural networks that are directly interfaced to electronic integrated circuits. . . and may lead to novel computational facilities.”
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
• Very simple design
• Scale is achievable
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Polyimide Picket Fences
Günther Zeck and Peter, Fromherz, PNAS, 2001 vol. 98, no. 18, 10457-10462
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Successful at immobilizing neurons, retains functionality
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Neurochip: 1 cm square,500 μm thick silicon wafer, with a 4x4 array of wells spacedon 100 μm centers
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
a) Neuron sucked in pipette
b) Cell ejected from pipette near a well
c) Pusher used to move cell over the well
d) Cell implanted in the well by means of the pusher
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
Advantages of parylene:
• Non-toxic, extremely inert, resistant to moisture
and most chemicals, and biocompatible
• Its conformal deposition makes it easy to
fabricate 3D structures like neuro-cage
• It is transparent: neurons can be seen through the cages
The cage consists of a top loadingaccess hole, the cage body, and6 thin channels for neuriteovergrowth
Zentrum für Mikro- und Nanotechnologien
Technische Universität Ilmenau, FG Nanotechnologie
1) Oxide layer is grown on silicon wafer
2) Channel height controlling sacrificial layer is
patterned
3) Two parylene and one photoresist layers are
used to form the cage
4) The sacrificial materials are removed to release
the microcage
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