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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



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

Biocompatibilty Issues:
• Toxicity and damage to tissue
• Functionality (Biofouling)
Electrically activated
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
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
http://www.bu.edu/mfg/programs/outreach/etseminars/2002may/documents/santini.pdf
Best Device
MicroCHIPS Inc. Implantable Device
http://www.ruf.rice.edu/~rau/phys600/1959.pdf
Why?
Why?
Many different configurations make it quite
Versatile
http://www.itnes.com/pages/batteries.html
Why?
Many different configurations make it quite
Versatile
Easy to implement
http://www.itnes.com/pages/batteries.html
Why?
Many different configurations make it quite
Versatile
Easy to implement
Simple yet effective
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”
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 etche
•KOH anisotropic etch (Silicon Nitride
acts as a mask and stop)
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
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
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
Thin Film Battery
No toxic materials used
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
Thin Film Battery
No toxic materials used
Nothing to leak into the body
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
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
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
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
Battery Cross Section
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
Actuation
http://www.njnano.org/pasi/event/talks/cima.pdf
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
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
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
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
http://www.njnano.org/pasi/event/talks/cima.pdf
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 nanochannels
• 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 = 6070nm, wall thickness =
10nm
Synthesis of PHSNP
involves CaCO3 template
Fig. 3. TEM (Transmission Electron Microscope) image of PHSNP
PHSNP to carry Cefradine
Treat bacterial infection
by destroying cell walls
Fig. 1. Molecular structure of cefradine.
Used for infection in
airways, kidneys, postsurgery, other
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.
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
drug delievery
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
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