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

Contents

• Technology• Productive Nanosystems

• Bio-mimetic• Scanning Probes

• Tip-Based Nanofabrication• Patterned Atomic Layer Epitaxy

• Application• Freitas Respirocytes• Requirements• Respirocyte subsystems

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

Protein engineering

Difficult: must solve protein folding problemSensitive to small changes in sequence or environmentLow temperature process, but low performance properties

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

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

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

Diamondoid Mechanosynthesis

Adding two carbon atoms at a timeTheory confirmed by 100,000 hours CPU time2009 experiment funded by UK EPSRC

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

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

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)

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

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.

Patterned Si ALE

Joe Lyding UIUC

Patterned Si ALE

Joe Lyding UIUC

Room Temperature10-8 Torr disilane10 minutes/row5V, 1nA; 7V .1nA; & 6V 1nA6nm high features

Tip ArraysTip Arrays MEMSMEMS 55,000 tips55,000 tips 15 nm resolution15 nm resolution FastFast

Freitas Respirocytes

Atomically Precise DiamondoidAtomically Precise Diamondoid 1000 nm (1 1000 nm (1 μμm); 1000 atmm); 1000 atm

Requirements Analysis: What & How

Subsystems

Red Blood Cell Function

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

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)

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)

Oligosaccharide and Rhesus Oligosaccharide and Rhesus Protein CoatingProtein Coating

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)

Respirocyte Subsystems

Pressure Vessels Pumps Power Communications Sensors Onboard Computation

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)

Location Dependent Pressure

Output O2

Input CO2

High-Pressure

Low-Pressure

Intake O2

Output CO2

Body TissueCapillaries

LungCapillaries

Ratiometric Oxygen NanosensorPEBBLE nanosensor Ruthenium-DPP

(Oxygen sensitive dye)

Oregon Green Dye

Nanoscale pH SensorNanoscale pH Sensor

Zinc Oxide NanowiresZinc Oxide Nanowires AlGaN/GaN junctionsAlGaN/GaN junctions Field tested outdoorsField tested outdoors

Selective Pumps

Water Pump

Neon Pump

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

Selective Oxygen Rotor

Oxygen bound

by Hemoglobin Oxygen re

leased

by Hemoglobin

Lower pH

higher temperature

mechanism

s

6 nm

Cascaded Selective RotorsBloodPlasma

Kinesin 2 ATP/cycle2 steps/cycle(rotation/slide)16 nm per cycle100 steps/second~5 picoNewtons40% efficient

Kinesin-based Motors

Glucose → ATP

Three out of 10 enzymes have been attached

PH

40% efficient

Carbon Dioxide Return

Carbonic anhydrase • 1 million times faster• 30,000 daltons

Issues:

Detecting CO2 presence

Getting CO2 out of heme

Bicarbonate Sequestering

CmpA Protein

Highly selective

452 residues ≈ 52,000 daltons

Selective Carbon Dioxide Rotor

CO2 catalyzed by

carbonic anhydrase

HCO 3

— released by

CmpA

Location

switch

5 nm

HCO3

— captured

by CmpA

Non-Selective Pumps

3-valve peristaltic Micropump

Piezoelectric

100 V (peak-to-peak)

100 Hz

17.6 microliters/minute

Selective Membranes

Denissov, Molecular Sieves for Gas Separating Membranes

Computation:Quantum Dot Cellular Automata

• Arbitrary Boolean logic• Single electron charge• Very low power consumption

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

Thank you!Thank you!

Questions?Questions?

Tihamer Toth-FejelTihamer.Toth-Fejel gd-ais.com