Respirocytes from Patterned Atomic Layer Epitaxy: The Most Conservative Pathway to the
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Respirocytes from Patterned Atomic Layer Epitaxy:
The Most Conservative Pathway to the Simplest Medical Nanorobot
Tihamer Toth-FejelTihamer.Toth-Fejel gd-ais.com
2nd Unither Nanomedical and Telemedicine Technology
ConferenceQuebec, Canada
February 24-27, 2009
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Contents
• Technology• Productive Nanosystems
• Bio-mimetic• Scanning Probes
• Tip-Based Nanofabrication• Patterned Atomic Layer Epitaxy
• Application• Freitas Respirocytes• Requirements• Respirocyte subsystems
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Productive Nanosystems
Size matters, atomic precision matters more.Automated nanoscale tools are most important.“A closed loop of nanoscale components that make
nanoscale components”
Approaches• Biomimetic methods
• Protein engineering• Bis-amino acid solid-phase self-assembly• Structural DNA
• Scanning Probe Techniques• Diamond Mechanosynthesis• Patterned Atomic Layer Epitaxy
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Protein engineering
Difficult: must solve protein folding problemSensitive to small changes in sequence or environmentLow temperature process, but low performance properties
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Bis-amino acid Solid-phase Self-assembly
• Protein engineering• Bis-amino acid Solid-phase Self-
assembly• Structural DNA
C. Schafmeister, Molecular Lego, Scientific American, Feb 2007, 64-71
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Structural DNA50 billion Smiley Faces in two hoursBy 1 person with a glorified kitchen oven
Paul W. K. Rothemund, Folding DNA to create nanoscale shapes and patterns, Nature Vol 440,16 March 2006 Courtesy Paul Rothemund
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Pixelated DNA and Positioning
courtesy Paul W. K. Rothemund Ke, et. al., Self-Assembled Water-Soluble Nucleic Acid Probe Tiles for Label-Free RNA Hybridization Assays, Science, Jan 11, 2008
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Diamondoid Mechanosynthesis
Adding two carbon atoms at a timeTheory confirmed by 100,000 hours CPU time2009 experiment funded by UK EPSRC
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Tip-Based NanofabricationTip-Based Nanofabrication
DARPA’s Goal:DARPA’s Goal:
Automated, parallel nanofabricationAutomated, parallel nanofabricationPosition, size, shape, and orientationPosition, size, shape, and orientation In-situ detection & repairIn-situ detection & repairAFM/STM or similar scanning probesAFM/STM or similar scanning probes
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TBN with LasersTBN with Lasers
3–5 ns pulse NSOM based
ablation FWHM of 90 nm Film of unsintered,
1–3 nm gold nanoparticle encapsulated by hexanethiol
300n
m
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TBN with Dip Pen Nanolithography: TBN with Dip Pen Nanolithography: Scanning Probe EpitaxyScanning Probe Epitaxy
Reader tip integrated with synthesis tip
Dual-tip scanning probes combine contact and non-contact modes
Core-filled tip with aperture controls nanostructure deposition
Control where, when, and how a reaction occurs on the nanometer scale
15 nm limit (so far)15 nm limit (so far)
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Tip-Based Nanofabrication:Atomically Precise Manufacturing
Produce 3D structures with top-down Produce 3D structures with top-down control and atomic precision. control and atomic precision.
Inevitable result of continued Inevitable result of continued improvements in ultra-precision improvements in ultra-precision manufacturingmanufacturing
Integration of known techniquesIntegration of known techniques
General manufacturing processGeneral manufacturing process
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Patterned Si ALE
STM tip removes H atoms from the Si surface
A precursor gas is used to dose the surface. Protected Si atoms are deposited only where H has been removed.
Completed deposition is verified and then the deprotection/patterning is repeated.
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Patterned Si ALE
Joe Lyding UIUC
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Patterned Si ALE
Joe Lyding UIUC
Room Temperature10-8 Torr disilane10 minutes/row5V, 1nA; 7V .1nA; & 6V 1nA6nm high features
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Tip ArraysTip Arrays MEMSMEMS 55,000 tips55,000 tips 15 nm resolution15 nm resolution FastFast
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Freitas Respirocytes
Atomically Precise DiamondoidAtomically Precise Diamondoid 1000 nm (1 1000 nm (1 μμm); 1000 atmm); 1000 atm
Requirements Analysis: What & How
Subsystems
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Red Blood Cell Function
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OO22 not soluble in water not soluble in water
Four hemes; one OFour hemes; one O22 each each 68,000 daltons68,000 daltons Lasts longer & more Lasts longer & more
effective inside cellseffective inside cells
HemoglobinHemoglobin
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Hemoglobin SaturationHemoglobin Saturation150 quintillion (10150 quintillion (101818) hemoglobin ) hemoglobin
molecules in 100 ml whole bloodmolecules in 100 ml whole bloodBinding regulated by O2 partial pressureBinding regulated by O2 partial pressure
Hem
oglo
bin
% S
atur
atio
nH
emog
lobi
n %
Sat
urat
ion
partial pressure oxygen (mm Hgpartial pressure oxygen (mm Hg)
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Hemoglobin Saturation: Bohr EffectHemoglobin Saturation: Bohr Effect
Lower pH -> lower saturationLower pH -> lower saturationHigher COHigher CO22 -> more oxygen delivered -> more oxygen deliveredHigher temperature also shifts curve rightHigher temperature also shifts curve right
Hem
oglo
bin
% S
atur
atio
nH
emog
lobi
n %
Sat
urat
ion
partial pressure oxygen (mm Hgpartial pressure oxygen (mm Hg)
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Oligosaccharide and Rhesus Oligosaccharide and Rhesus Protein CoatingProtein Coating
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PerfluorocarbonsPerfluorocarbonsPFCs dissolve > 100x OPFCs dissolve > 100x O22 than blood serum than blood serum
PFCs are hydrophobic & require emulsifiersPFCs are hydrophobic & require emulsifiers
Perfluorocarbons surrounded by Perfluorocarbons surrounded by a surfactant (lecithin)a surfactant (lecithin)
Up to twice as efficient as RBC Up to twice as efficient as RBC (at high partial pressure)(at high partial pressure)
No refrigeration requiredNo refrigeration required 1/401/40thth size of RBC size of RBC May increase risk of stroke in May increase risk of stroke in
cardiac patientscardiac patients Short term (hours)Short term (hours)
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Respirocyte Subsystems
Pressure Vessels Pumps Power Communications Sensors Onboard Computation
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1000 nm Spherical Pressure Vessels
APM Diamond 1,000,000 MPa 5 nm (~30 carbon atoms) walls10,000 atm (but diminishing returns after 1000 atm)
Silicon (Crystalline, low defects)30,000 MPa10 nm walls1,400 atm
Blood cells (or serum PFCs)0.51 atm0.13 atm deliverable to tissues (less for PFCs)
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Location Dependent Pressure
Output O2
Input CO2
High-Pressure
Low-Pressure
Intake O2
Output CO2
Body TissueCapillaries
LungCapillaries
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Ratiometric Oxygen NanosensorPEBBLE nanosensor Ruthenium-DPP
(Oxygen sensitive dye)
Oregon Green Dye
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Nanoscale pH SensorNanoscale pH Sensor
Zinc Oxide NanowiresZinc Oxide Nanowires AlGaN/GaN junctionsAlGaN/GaN junctions Field tested outdoorsField tested outdoors
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Selective Pumps
Water Pump
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Neon Pump
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Selective Pump:Combined motor and rotor
Sodium-Potassium Exchange Pump• Small (12 nm diameter)• 17 RMP (no load)• 100 picoNewtons• Runs on ATP • Elegant • Difficult to integrate with silicon shell
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Selective Oxygen Rotor
Oxygen bound
by Hemoglobin Oxygen re
leased
by Hemoglobin
Lower pH
higher temperature
mechanism
s
6 nm
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Cascaded Selective RotorsBloodPlasma
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Kinesin 2 ATP/cycle2 steps/cycle(rotation/slide)16 nm per cycle100 steps/second~5 picoNewtons40% efficient
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Kinesin-based Motors
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Glucose → ATP
Three out of 10 enzymes have been attached
PH
40% efficient
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Carbon Dioxide Return
Carbonic anhydrase • 1 million times faster• 30,000 daltons
Issues:
Detecting CO2 presence
Getting CO2 out of heme
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Bicarbonate Sequestering
CmpA Protein
Highly selective
452 residues ≈ 52,000 daltons
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Selective Carbon Dioxide Rotor
CO2 catalyzed by
carbonic anhydrase
HCO 3
— released by
CmpA
Location
switch
5 nm
HCO3
— captured
by CmpA
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Non-Selective Pumps
3-valve peristaltic Micropump
Piezoelectric
100 V (peak-to-peak)
100 Hz
17.6 microliters/minute
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Selective Membranes
Denissov, Molecular Sieves for Gas Separating Membranes
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Computation:Quantum Dot Cellular Automata
• Arbitrary Boolean logic• Single electron charge• Very low power consumption
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Production IssuesProduction Issues
By 2012: Ten million atoms/hour (silicon)By 2012: Ten million atoms/hour (silicon) Nanoimprint lithographyNanoimprint lithography Multiple materials Multiple materials ALE does not work for complex proteinsALE does not work for complex proteins BootstrappingBootstrapping
Small STM arrays build larger STM arraysSmall STM arrays build larger STM arraysBuild fabrication and assembly linesBuild fabrication and assembly lines
Smaller vacuum chambersSmaller vacuum chambers
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Thank you!Thank you!
Questions?Questions?
Tihamer Toth-FejelTihamer.Toth-Fejel gd-ais.com