BioMEMS Implantable Drug Delivery Systems

Professor Horacio Espinosa ME381 Final project

Aaron Alexander Luke Rogers Dan Sheehan

Brent Willson

Current Technology
Include hypodermic needles, pills, and passive transdermal methods Disadvantages:

Highly Invasive Poor Control Can be Ineffective

Drug Delivery by MEMS

Advantages

Disadvantages

Improved Control More Effective Less Intrusive

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

Active

Pourous material allows diffusion Deteriorating membranes

Electrically activated

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

Passive vs. Active

Passive

Active

Simpler to manufacture No power source needed Less control

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

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 Device
MicroCHIPS Inc. Implantable Device

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

Best Device
MicroCHIPS Inc. Implantable Device

11 http://www.ruf.rice.edu/~rau/phys600/1959.pdf

Why?

12

Why?
Many different configurations make it quite Versatile

13 http://www.itnes.com/pages/batteries.html

Why?
Many different configurations make it quite Versatile Easy to implement

14 http://www.itnes.com/pages/batteries.html

Why?
Many different configurations make it quite Versatile Easy to implement Simple yet effective

15 http://www.itnes.com/pages/batteries.html

Why?
Many different configurations make it quite Versatile Easy to implement Simple yet effective Smaller in size than the Smart Pill

16 http://www.itnes.com/pages/batteries.html

Start with Silicon wafer approx. 300 microns thick PECVD 3000 angstrom thick Silicon Nitride

Silicon Nitride Patterned with Photolithography and RIE etched

KOH anisotropic etch (Silicon Nitride acts as a mask and stop)

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

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

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

Invert and inject drug into reservoir using inkjet technology

Reservoirs capped with Silicon Nitride

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

Steps following fabrication

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

20

Thin Film Battery

No toxic materials used

21 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

Thin Film Battery

No toxic materials used Nothing to leak into the body

22 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

Thin Film Battery

No toxic materials used Nothing to leak into the body Can be recharged many times

23 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

Thin Film Battery

No toxic materials used Nothing to leak into the body Can be recharged many times 1.5 to 4.5 volts

24 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

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:

.5 to 25 cm2 15 microns thick

25 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

Battery Cross Section

26 http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm

Actuation

http://www.njnano.org/pasi/event/talks/cima.pdf 27

Oxidation Reduction Reaction

Au + 4Cl- [AuCl4]- + 3eAu + mH2O [Au(H2O)m]3+ + 3e2Au + 3H2O Au2O3 + 6H+ + 6e2Cl- Cl2 +2eAu2O3 + 8Cl- + 6H+ 2[AuCl4]- +3H2O
http://ocw.mit.edu/NR/rdonlyres/Biological-Engineering-Division/BE-462JMolecular-Principles-ofBiomaterialsSpring2003/3B2F94CD-4C8D-456C-93F4-CF10C63BB014/0/BE462lect06.pdf 28

Activation of Redox Reaction

The in vivo environment can be considered as an aqueous NaCl solution with a PH between 6 and 7 When a minimum of .8V is applied [AuCl4]- is the favorable state for gold in this solution.
http://ocw.mit.edu/NR/rdonlyres/Biological-Engineering-Division/BE-462JMolecular-Principles-ofBiomaterialsSpring2003/3B2F94CD-4C8D-456C-93F4-CF10C63BB014/0/BE462lect06.pdf 29

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
http://www.njnano.org/pasi/event/talks/cima.pdf 30

Oxidation (corrosion) of Gold Reservoir Caps

A stimulus voltage is applied for 10-50 s to start the oxidation reaction Gold corrodes and goes into the body as harmless [AuCl4]-

http://www.njnano.org/pasi/event/talks/cima.pdf 31

Gold Reservoir Cap

http://www.njnano.org/pasi/event/talks/cima.pdf 32

Developing Technology
Nano-channel Device Porous Hollow Silica Nanoparticles (PHSNP) Quantum Dots

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Nano-channel Device

Nano-channel filter Simpler than previous devices Standard/Mass production Dimensions optimized for strength
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Top of Base Substrate

Drug enters entry flow chamber from entry port of top substrate
Enters input fingers, passes through nanochannels Exits through output fingers and exit flow chamber

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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

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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 = 6070nm, wall thickness = 10nm Synthesis of PHSNP involves CaCO3 template
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Fig. 3. TEM (Transmission Electron Microscope) image of PHSNP

PHSNP to carry Cefradine

Treat bacterial infection by destroying cell walls Used for infection in airways, kidneys, postsurgery, other

Fig. 1. Molecular structure of cefradine.

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Distribution of Cefradine in PHSNP

PHSNP and Cefradine mixed vigorously
Fig. 2. Preparation process of drug carrier from PHSNP. (a) PHSNP; (b) suspension of cefradine and PHSNP; (c) PHSNP entrapped with cefradine.

Fig. 4. Distribution of pore diameters in the wall of PHSNP (a) before entrapping cefradine; (b) after entrapping cefradine.

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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
Fig. 5. In vitro release profile of cefradine from PHSNP

Gradual release over time can be exploited in 40

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 and can be targeted Once excited with IR light, the bond is broken with the drug, Taxol, which is able to attack the cancerous cell
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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
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