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BioMEMS Implantable Drug BioMEMS Implantable Drug Delivery SystemsDelivery Systems
Professor Horacio Espinosa – ME381 – Final projectProfessor Horacio Espinosa – ME381 – Final project
Aaron AlexanderAaron Alexander
Luke RogersLuke Rogers
Dan SheehanDan Sheehan
Brent WillsonBrent Willson
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Current TechnologyCurrent Technology
Include hypodermic needles, pills, and Include hypodermic needles, pills, and passive transdermal methodspassive transdermal methods
Disadvantages:Disadvantages: Highly InvasiveHighly Invasive Poor ControlPoor Control Can be IneffectiveCan be Ineffective
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Drug Delivery by MEMSDrug Delivery by MEMS
AdvantagesAdvantages Improved ControlImproved Control More EffectiveMore Effective Less IntrusiveLess Intrusive
DisadvantagesDisadvantages Biocompatibility Biocompatibility
ConcernsConcerns Biofouling IssuesBiofouling Issues
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Areas of ResearchAreas of Research
In Vivo DevicesIn Vivo Devices Within the bodyWithin the body Implanted or IngestedImplanted or Ingested
Transdermal DevicesTransdermal Devices Acts through the skinActs through the skin
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Reservoir DevicesReservoir Devices
PassivePassive Pourous material Pourous material
allows diffusionallows diffusion Deteriorating Deteriorating
membranesmembranes
ActiveActive Electrically activatedElectrically activated
Biocompatibilty Issues:• Toxicity and damage to tissue• Functionality (Biofouling)
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Passive vs. ActivePassive vs. Active
PassivePassive Simpler to Simpler to
manufacturemanufacture No power source No power source
neededneeded Less controlLess control
ActiveActive More complex More complex
fabricationfabrication Battery requiredBattery required More biocompatibility More biocompatibility
concernsconcerns Much more controlMuch more control Several means to Several means to
stimulate actuationstimulate actuation
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The “Smart Pill”The “Smart Pill”
Built-in sensor to detect when the drug is Built-in sensor to detect when the drug is requiredrequired
Artificial muscle membrane to release the Artificial muscle membrane to release the drugdrug
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Transdermal DevicesTransdermal Devices
Currently available:Currently available: PassivePassive
Can be ineffective and difficult to controlCan be ineffective and difficult to control
Improvements:Improvements: IontophoresisIontophoresis Chemical EnhancersChemical Enhancers UltrasoundUltrasound
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MicroneedlesMicroneedles
Microneedles are used to improve Microneedles are used to improve transdermal drug deliverytransdermal drug delivery
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Best DeviceBest Device
MicroCHIPS Inc. Implantable DeviceMicroCHIPS Inc. Implantable Device
http://www.bu.edu/mfg/programs/outreach/etseminars/2002may/documents/santini.pdf
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Best DeviceBest Device
MicroCHIPS Inc. Implantable DeviceMicroCHIPS Inc. Implantable Device
http://www.ruf.rice.edu/~rau/phys600/1959.pdf
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Why?Why?
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Why?Why?
Many different configurations make it quite Many different configurations make it quite VersatileVersatile
http://www.itnes.com/pages/batteries.html
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Why?Why?
Many different configurations make it quite Many different configurations make it quite VersatileVersatile
Easy to implementEasy to implement
http://www.itnes.com/pages/batteries.html
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Why?Why?
Many different configurations make it quite Many different configurations make it quite VersatileVersatile
Easy to implementEasy to implement
Simple yet effectiveSimple yet effective
http://www.itnes.com/pages/batteries.html
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Why?Why?
Many different configurations make it quite Many different configurations make it quite VersatileVersatile
Easy to implementEasy to implement
Simple yet effectiveSimple yet effective
Smaller in size than the “Smart Pill”Smaller in size than the “Smart Pill”
http://www.itnes.com/pages/batteries.html
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•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
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•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
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•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
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Steps following fabricationSteps following fabrication
Integrated Circuitry manufacturedIntegrated Circuitry manufactured
Combined with delivery chip and thin film Combined with delivery chip and thin film battery into a compact package battery into a compact package
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Thin Film BatteryThin Film Battery
No toxic materials usedNo toxic materials used
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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Thin Film BatteryThin Film Battery
No toxic materials usedNo toxic materials used
Nothing to leak into the bodyNothing to leak into the body
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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Thin Film BatteryThin Film Battery
No toxic materials usedNo toxic materials used
Nothing to leak into the bodyNothing to leak into the body
Can be recharged many timesCan be recharged many times
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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Thin Film BatteryThin Film Battery
No toxic materials usedNo toxic materials used
Nothing to leak into the bodyNothing to leak into the body
Can be recharged many timesCan be recharged many times
1.5 to 4.5 volts1.5 to 4.5 volts
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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Thin Film BatteryThin Film Battery
No toxic materials usedNo toxic materials used
Nothing to leak into the bodyNothing to leak into the body
Can be recharged many timesCan be recharged many times
1.5 to 4.5 volts1.5 to 4.5 volts
Size:Size: .5 to 25 cm.5 to 25 cm22
15 microns thick15 microns thick
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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Battery Cross Section
http://www.ssd.ornl.gov/Programs/BatteryWeb/index.htm
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ActuationActuation
http://www.njnano.org/pasi/event/talks/cima.pdf
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Oxidation Reduction ReactionOxidation Reduction Reaction
Au + 4Cl- Au + 4Cl- [AuCl4]- + 3e- [AuCl4]- + 3e- Au + mH2O Au + mH2O [Au(H2 O)m]3+ + 3e- [Au(H2 O)m]3+ + 3e-2Au + 3H2O 2Au + 3H2O Au2O3 + 6H+ + 6e- Au2O3 + 6H+ + 6e-2Cl- 2Cl- Cl2 +2e- Cl2 +2e-Au2O3 + 8Cl- + 6H+ Au2O3 + 8Cl- + 6H+ 2[AuCl4]- +3H2O 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
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Activation of Redox ReactionActivation of Redox Reaction
The The in vivoin vivo environment can be environment can be considered as an considered as an aqueous NaCl aqueous NaCl solution with a PH solution with a PH between 6 and 7 between 6 and 7 When a minimum When a minimum of .8V is applied of .8V is applied [AuCl4][AuCl4]-- is the is the favorable state for favorable state for gold in this solution. 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
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Advantage of Implantable Drug Advantage of Implantable Drug Delivery Delivery
Conventional drug Conventional drug delivery such as injection delivery such as injection or pillsor pills
Much farther from the Much farther from the ideal concentration over ideal concentration over the time cyclethe time cycle
MEMS implantable drug MEMS implantable drug delivery systemsdelivery systems
Maintains a dosage level Maintains a dosage level very close to the target very close to the target rate rate
http://www.njnano.org/pasi/event/talks/cima.pdf
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Oxidation (corrosion) of Gold Oxidation (corrosion) of Gold Reservoir CapsReservoir Caps
A stimulus voltage is A stimulus voltage is applied for 10-50 µs applied for 10-50 µs to start the oxidation to start the oxidation reactionreaction
Gold corrodes and Gold corrodes and goes into the body as goes into the body as harmless [AuCl4]- harmless [AuCl4]-
http://www.njnano.org/pasi/event/talks/cima.pdf
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Gold Reservoir CapGold Reservoir Cap
http://www.njnano.org/pasi/event/talks/cima.pdf
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Developing TechnologyDeveloping Technology Nano-channel DeviceNano-channel Device Porous Hollow Silica Porous Hollow Silica Nanoparticles (PHSNP)Nanoparticles (PHSNP) Quantum DotsQuantum Dots
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Nano-channel DeviceNano-channel Device
Nano-channel Nano-channel filterfilter
Simpler than Simpler than previous devicesprevious devices
Standard/Mass Standard/Mass productionproduction
Dimensions Dimensions optimized for optimized for strengthstrength
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Top of Base SubstrateTop 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
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Glucose ReleaseGlucose Release
Solution to constant Solution to constant drug delivery needdrug delivery need
Drawback: drugs pass Drawback: drugs pass through nano-channels through nano-channels at different rates – at different rates – electrical integration electrical integration and control of flow and control of flow through nano-channelsthrough nano-channels
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Porous Hollow Silica Nanoparticles Porous Hollow Silica Nanoparticles
(PHSNP)(PHSNP) Used in many different Used in many different applicationsapplicationsPast drug carriers Past drug carriers primarily oil-in-water primarily oil-in-water units, liposomes, and units, liposomes, and nanoparticles and nanoparticles and microparticles made of microparticles made of synthetic polymers and or synthetic polymers and or natural macromoleculesnatural macromoleculesPHSNP diameter = 60-PHSNP diameter = 60-70nm, wall thickness = 70nm, wall thickness = 10nm10nmSynthesis of PHSNP Synthesis of PHSNP involves CaCO3 templateinvolves CaCO3 template
Fig. 3. TEM (Transmission Electron Microscope) image of PHSNP
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PHSNP to carry CefradinePHSNP to carry Cefradine
Treat bacterial infection Treat bacterial infection by destroying cell wallsby destroying cell walls
Used for infection in Used for infection in airways, kidneys, post-airways, kidneys, post-surgery, othersurgery, other
Fig. 1. Molecular structure of cefradine.
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Distribution of Cefradine in PHSNPDistribution of Cefradine in PHSNP
Fig. 4. Distribution of pore diameters in the wall of PHSNP (a) before entrapping cefradine; (b) after entrapping cefradine.
Fig. 2. Preparation process of drug carrier from PHSNP. (a) PHSNP; (b) suspension of cefradine and PHSNP; (c) PHSNP entrapped with cefradine.
•PHSNP and Cefradine mixed vigorously
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Release of CefradineRelease of Cefradine
Stage oneStage one: 76% release in : 76% release in 20 min. – surface of PHSNP20 min. – surface of PHSNPStage twoStage two: 76%-82% : 76%-82% release in 10 hours– pores release in 10 hours– pores of PHSNPof PHSNPStage threeStage three: insignificant : insignificant release from PHSNP hollow release from PHSNP hollow centercenter
Gradual release over time Gradual release over time can be exploited in drug can be exploited in drug delievery applicationsdelievery applications
Fig. 5. In vitro release profile of cefradine from PHSNP
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Quantum DotsQuantum Dots
Crystals containing a group of electrons – usually made Crystals containing a group of electrons – usually made of II-VI semiconductor cadmium selenideof II-VI semiconductor cadmium selenideNanometers wide, demonstrate quantum properties of Nanometers wide, demonstrate quantum properties of single atoms, absorb and emit specific wavelengths of single atoms, absorb and emit specific wavelengths of lightlightBind Taxol, a cancer-fighting drug, and a molecule with Bind Taxol, a cancer-fighting drug, and a molecule with affinity to folic acid receptors to quantum dots, also affinity to folic acid receptors to quantum dots, also effective when bound with antibodieseffective when bound with antibodiesCancer cells have high concentration of folic acid Cancer cells have high concentration of folic acid receptors and can be targetedreceptors and can be targetedOnce excited with IR light, the bond is broken with the Once excited with IR light, the bond is broken with the drug, Taxol, which is able to attack the cancerous celldrug, Taxol, which is able to attack the cancerous cell
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IR Illuminated RatIR Illuminated Rat
Implanted with tumorImplanted with tumor
Injected with quantum dots, Injected with quantum dots, bound with Taxolbound with Taxol
High concentration around High concentration around tumortumor
Technique not as effective in Technique not as effective in humans due to deep internal humans due to deep internal organsorgans
May be effective for skin and May be effective for skin and breast cancerbreast cancer