BIO-MEMS DEVICES 1) DRUG TO CELL (OR BODY), 2) CELL TO DRUG€¦ · The “Smart Pill” • Built-in sensor to detect when the drug is required ... • Combined with delivery chip

Zentrum für Mikro- und Nanotechnologien

Technische Universität Ilmenau, FG Nanotechnologie

BIO-MEMS DEVICES

1) DRUG TO CELL (OR BODY), 2) CELL TO DRUG



Current Technology for Drug Delivery

• Include hypodermic needles, pills, and passive transdermalmethods

• Disadvantages:– Highly Invasive– Poor Control– Can be Ineffective



Drug Delivery by MEMS

• Advantages– Improved Control– More Effective– Less Intrusive

• Disadvantages– Biocompatibility Concerns– Biofouling Issues



Areas of Research

• In Vivo Devices– Within the body– Implanted or Ingested

• Transdermal Devices– Acts through the skin



Reservoir Devices

• Passive– Pourous material allows

diffusion– Deteriorating membranes

• Active– Electrically activated

Biocompatibilty Issues:• Toxicity and damage to tissue• Functionality (Biofouling)



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



The “Smart Pill”

• Built-in sensor to detect when the drug is required• Artificial muscle membrane to release the drug



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



Transdermal Devices

• Currently available:– Passive

• Can be ineffective and difficult to control• Improvements:

– Iontophoresis– Chemical Enhancers– Ultrasound



Microneedles

• Microneedles are used to improve transdermal drug delivery



Best DeviceMicroCHIPS Inc. Implantable Device

http://www.bu.edu/mfg/programs/outreach/etseminars/2002may/documents/santini.pdf



Best Device

MicroCHIPS Inc. Implantable Device



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



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)



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



Invert and inject drug into reservoir using inkjet technology

Reservoirs capped with silicon nitride



Actuation



Steps following fabrication

• Integrated Circuitry manufactured• Combined with delivery chip and thin film battery into a

compact package



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



Battery Cross Section



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



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



Gold Reservoir Cap



Developing Technology

• Nano-channel Device

• Porous Hollow Silica Nanoparticles (PHSNP)• Quantum Dots



Nano-channel Device

• Nano-channel filter• Simpler than

previous devices• Standard/Mass

production• Dimensions

optimized for strength



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



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



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



PHSNP to carry Cefradine

• Treat bacterial infection by destroying cell walls

• Used for infection in airways, kidneys, post-surgery, other

Molecular structure of cefradine.



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.



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



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





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



• Planar monitoring system

• Neurons cage array

• Living chips with peptide amphiphiles gels



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.”





• Very simple design

• Scale is achievable









Polyimide Picket Fences

Günther Zeck and Peter, Fromherz, PNAS, 2001 vol. 98, no. 18, 10457-10462



Successful at immobilizing neurons, retains functionality



Neurochip: 1 cm square,500 μm thick silicon wafer, with a 4x4 array of wells spacedon 100 μm centers



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



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



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





Conclusions:

• Parylene has been shown to be biocompatible

• The parylene neurocages are mechanically

functional

Documents

BIO-MEMS DEVICES 1) DRUG TO CELL (OR BODY), 2) CELL TO DRUG€¦ · The “Smart Pill” • Built-in sensor to detect when the drug is required ... • Combined with delivery chip