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 Disadvantages Biocompatibility Concerns Biofouling Issues

Areas of Research In Vivo Devices Transdermal Devices Within the body Implanted or Ingested Transdermal Devices Acts through the skin

Reservoir Devices Passive Active Pourous material allows diffusion Deteriorating membranes Active 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 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: Improvements: Passive Can be ineffective and difficult to control Improvements: Iontophoresis Chemical Enhancers Ultrasound

Microneedles Microneedles are used to improve transdermal drug delivery

MicroCHIPS Inc. Implantable Device Best Device MicroCHIPS Inc. Implantable Device http://www.bu.edu/mfg/programs/outreach/etseminars/2002may/documents/santini.pdf

MicroCHIPS Inc. Implantable Device 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 etched 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]- + 3e- Au + mH2O  [Au(H2­O)m]3+ + 3e- 2Au + 3H2O  Au2O3 + 6H+ + 6e- 2Cl-  Cl2 +2e- Au2O3 + 8Cl- + 6H+  2[AuCl4]- +3H2O http://ocw.mit.edu/NR/rdonlyres/Biological-Engineering-Division/BE-462JMolecular-Principles-of-BiomaterialsSpring2003/3B2F94CD-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-of-BiomaterialsSpring2003/3B2F94CD-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 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 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, post-surgery, other Fig. 1. Molecular structure of cefradine.

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 Gradual release over time can be exploited in drug delievery applications Fig. 5. 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 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