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

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

Drug Delivery by MEMSDrug Delivery by MEMS

AdvantagesAdvantages Improved ControlImproved Control More EffectiveMore Effective Less IntrusiveLess Intrusive

DisadvantagesDisadvantages Biocompatibility Biocompatibility

ConcernsConcerns Biofouling IssuesBiofouling Issues

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

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)

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

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

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

MicroneedlesMicroneedles

Microneedles are used to improve Microneedles are used to improve transdermal drug deliverytransdermal drug delivery

Best DeviceBest Device

MicroCHIPS Inc. Implantable DeviceMicroCHIPS Inc. Implantable Device

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

Best DeviceBest Device

MicroCHIPS Inc. Implantable DeviceMicroCHIPS Inc. Implantable Device

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

Why?Why?

Why?Why?

Many different configurations make it quite Many different configurations make it quite VersatileVersatile

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

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

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

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

•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 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

Thin Film BatteryThin Film Battery

No toxic materials usedNo toxic materials used

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

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

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

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

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

Battery Cross Section

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

ActuationActuation

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

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

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

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

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

Gold Reservoir CapGold Reservoir Cap

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

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

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

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

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

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

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.

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

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

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

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