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Nanotechnology, Nanoparticlesand Nanononsense
Mark Bumiller
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Definitions*nanoparticle, n—in nanotechnology, a sub-classification of ultrafine particle with lengths in two or three dimensions greater than 0.001 micrometer (1 nanometer) and smaller than about 0.1 micrometer (100 nanometers) and which may or may not exhibit a size-related intensive propertyfine particle, n—in nanotechnology, a particle smaller than about 2.5 micrometers and larger than about 0.1 micrometers in sizeultrafine particle, n—in nanotechnology, a particle ranging in size from approximately 0.1 micrometer (100 nanometers) to .001 micrometers (1 nanometer).
*ASTM E 2456-06 Standard Terminology Relating to Nanotechnology
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The Lycurgus Cup - Late Roman, 4th century AD
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The Lycurgus Cup - Late Roman, 4th century AD
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Gold Nanoparticles
Gustav Mie, Ann. Physik25, 377 (1908)
Surface Plasmon Resonance
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Gold Nanoparticles In Use
Pregnant women have excess of hormone HcG*HcG binds to complementary DNA base pair sequenceThat lock for HcG key is attached to gold nanoparticlesThose gold nanoparticles reflect light of specific colorIf HcG detected: line reflects red
*human gonadotropic hormone
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Foreseen in 1959 by Richard Feynman
The first use of the concepts in 'nano-technology' (but predating use of that name) was in "There's Plenty of Room at the Bottom," a talk given by physicist Richard Feynman at an American Physical Societymeeting at Caltech on December 29, 1959
But I am not afraid to consider the final question as to whether, ultimately---in the great future---we can arrange the atoms the way we want; the very atoms, all the way down! What would happen if we could arrange the atoms one by one the way we want them
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First Used in 1974 Paper in Japan
The term "nanotechnology" was defined by Tokyo Science UniversityProfessor Norio Taniguchi in a 1974paper*:
“Nano-technology” mainly consists of the processing of, separation, consolidation, and deformation of materials by one atom or by one molecule.
*N. Taniguchi, "On the Basic Concept of 'Nano-Technology'," Proc. Intl. Conf. Prod. Eng. Tokyo, Part II, Japan Society of Precision Engineering, 1974.
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What is Nanotechnology?So what is Nanotechnology?*
Nanotechnology is the understanding and control of matter at dimensions between approximately 1 and 100 nanometers, where unique phenomena enable novel applications. Encompassing nanoscale science, engineering, and technology, nanotechnology involves imaging, measuring, modeling, and manipulating matter at this length scale.
LA-950: 30nm – 3 mm LB-550 3 nm- 1 µm DT-1201 3 nm – 300 µm
Where does HORIBA fit in?
* From: http://www.nano.gov/html/facts/whatIsNano.html
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National Nanotechnology Initiative (NNI)
Established in 2001Framework for a comprehensive nanotechnology R&D programFoster transfer of new technologies into productsDevelop & sustain educational resources, a skilled workforce, and the supporting infrastructure and tools to advance nanotechnology.
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NNI Research Centers
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Scale
1 nm
100 μmX 100,000
Carbon nanotube D=1nm Human hair D=100 μm= 100,000 nm
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What is Nanotechnology?
Dry: Fabrication of structures in carbon, silicon, other inorganics (nanoparticles)
Wet: Biological systems in a water environment. Genes, proteins, enzymes (biotechnology)
Computational: modeling & simulation (university research)
10 nm
2 nm
X
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Industry Focus
MicroElectroMechanical (MEMS) devices
X
X
X
No
Yes
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Companies & StocksMerrill Lynch Nanotechnology Index*
*Update 7/21/09 divide all values by (at least)2
LA-950 Customer: Nanophase
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Companies & StocksLux Nanotech Index*
* From www.luxresearchinc.com
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Companies & StocksLux Nanotech Index
Component Name Ticker Sector Value Chain StageAccelrys ACCL Electronics and IT NanotoolsAltair Nanotechnologies ALTI Materials and manufacturing NanomaterialsAmerican Pharmaceutical Partners APPX Healthcare and life sciences Nano-enabled productsArrow head Research ARWR [Proxy for multiple sectors] [Proxy for multiple stages]Elan ELN Healthcare and life sciences Nano-enabled productsFEI Company FEIC Electronics and IT NanotoolsFlamel Technologies FLML Healthcare and life sciences Nano-enabled productsHeadw aters HW Materials and manufacturing NanointermediatesNanophase Technologies NANX Materials and manufacturing NanomaterialsNanosphere NSCH Healthcare and life sciences Nano-enabled productsNVE NVEC Electronics and IT NanointermediatesSymyx Technologies SMMX Materials and manufacturing NanotoolsHarris & Harris Group TINY [Proxy for multiple sectors] [Proxy for multiple stages]Veeco Instruments VECO Electronics and IT Nanotools
Nanotech Specialists
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Companies & StocksLux Nanotech Index
Component Name Ticker Sector Value Chain Stage
Air Products & Chemicals APD Materials and Manufacturing Nanointermediates
Company DD Materials and Manufacturing Nanointermediates
General Electric GE Materials and Manufacturing Nano-enabled products
Hew lett-Packard HPQ Electronics and IT Nano-enabled products
Intel INTC Electronics and IT Nano-enabled products
Machines IBM Electronics and IT Nano-enabled products
Toyota TM Materials and Manufacturing Nano-enabled products
3M MMM Materials and ManufacturingNanointermediates, nano-enabled products
End-Use Incumbents
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Making Nanoparticles
Top DownMake particles smaller
Bottom UpBuild from atomic or molecular level up
Self assembly of micelles
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Drug Particles
Many new chemical entities (NCEs) are poorly water solubleAdvances in Drug Discovery (high throughput screening) produce 30%-50% poorly water soluble leadsElan-NanoSystems™technology reduces the particle size of a poorly water soluble drug from several microns to ~50 nmReduction in particle size results in an increase in surface area Assumption:30% of discovery actives are water insoluble & not
evaluated in animal studies because of formulation problems
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Dissolution & Particle Sizedc = k S ( Cs – Ct)dt
dc/dt = rate of dissolutionk = dissolution rate constantS = surface area of dissolving drugCs = saturation concentration of drug in diffusion layerCt = concentration of drug in dissolution medium @ time t
To increase dissolution rate:S may be easiest parameter to adjustDecrease particle size, increases surface area
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Oral Absorption of Poorly Soluble Drugs
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Blood Absorption Profile
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Top Down: Elan NanoMill
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Top Down: Elan NanoMill
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Size Reduction Measured on LA-950
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Top Down: Microfluidizer*
Continuous processing Accommodates materials with high solid contentCertain models accommodate two separate stream feeds
High pressure used to deliver product into the interaction chamberConstant pressure pumping system
Microchannels range from 50-500 micronsUnsurpassed shear and impact forces Temperature regulated by a heat exchangerLack of moving parts maximizes uptimeRepeatable and scalable results
`
* See http://www.microfluidicscorp.com/
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Top Down: MicrofluidizerParticle size reduction – Colitis drug nanoemulsion
Median particle size (D50) after processing: 385 nm
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Top Down: MicrofluidizerParticle size reduction – Ophthalmic drug delivery nanoemulsion
Median particle size (D50) after 1 pass @ 24,000 psi: 96 nm
1 pass
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Bottom Up:Microfluidics Reaction Technology (MRT)
90-332Loratadine
1,2005,000x20,000767Oxcarbazepine
4283,000x1,000,000180Norfloxacin
Top-down Particle Size Reduction25 Passes (nm)
Beaker Bottom-up Crystallization
(nm)
MRT Bottom-up Crystallization
1 Pass (nm)
APIApplications of MRT• Crystallization• Nanoencapsulation• Chemical reactions• Process intensification
Reactant 1 Intensifier pump
Heat exchanger
Outlet
Impinging jet
chamber
Reactant 2
Pressures up to 40,000 psi
(2758 bar)
Feed pumps
Novel combination of bottom-up process development and an impinging jet processor achieves unparalleled and unprecedented results
0
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10 100 1000
Particle size (nm)
Freq
uenc
y (v
ol. %
)
200 nm
Report: AzithromycinZ-average particle size: 82 nm
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LA-950
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Low End Sensitivity
30, 40, 50, 70 nm latex standards
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Low End Sensitivity
Sensitivity: small particle detection30 nm silica 40 nm latex
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Nanoparticles for Drug Delivery“Engineered Particles”
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Bind Biosciences*
Targeting ligand provides recognition, enabling targeted nanoparticles to identify and bind to their intended target site.Surface functionalization shields targeted nanoparticles from the immune system.Polymer matrix encapsulates payload molecules in a matrix of biodegradable polymers .Therapeutic payloads include small molecules, peptides, proteins, etc.
* Cambridge, MA, recent LA-950 customer
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Bob Langer (MIT Professor)
600 patents, sublicensed to over 200 pharmaceutical/biotech companies, almost all particle technology relatedFounded over 24 companies (so far)160 major awards: National Medal of Science, National Inventors Hall of Fame, National Academy of Engineering and the National Academy of Sciences (at age 43)
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Quantum Dots
2nm 6 nm
5-75 atoms in diameter
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Quantum Dots Applications
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Self Assembly: MicellesHydrophobic tail Hydrophilic head
R +/-non polar polar
hates water loves water
-c-h-c-h-c-h-
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Liposomes
100 nm
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DLS Application : Liposomes
Liposome particle size after 5 passes through a 100 mm membrane ~ 250 nm
Liposome particle size after 20 passes through a 100 mm membrane ~ 150 nm
LB-550 DLS System
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FDA Approved Liposome: Doxil
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FDA Approved Nanoparticle: Abraxane
Nanoparticle formulation of the chemotherapy drug paclitaxel and the protein albuminMore effective and less toxic than the free form of the drug
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Fullerenes
C60: Buckyballs
cylindrical fullerene:carbon nanotube
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Carbon Nanotubes
2 nm 200nm
Discovered by:Sumio Iijima , 1991
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Carbon Nanotube Applications
StructuralBulletproof vests, waterproof & tear resistant clothes, concrete, space elevator
Electromagnetic & circuitsNanowire, transistors, superconductors
ChemicalFilters, hydrogen storage
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Particle Stability
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Particle Stability: DT-1200
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Stability in Action*
The nanofiller particles in Adper™ Single Bond Plus Adhesive are added in a manner that does not allow them to cluster together.The particles are stable and will not settle out of dispersion. So unlike some filled adhesives, Adper Single Bond Plus adhesive does not require shaking prior to use. *http://solutions.3m.com/wps/portal/3M/en_US/3M-ESPE/dental-professionals/products/category/bonding/adper-single-bond-plus/
5 nm particles 400 nm particles
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Nanoparticle Safety: Cosmetics
“Preliminary scientific research has shown that many types of nanoparticles can be toxic to human tissue and cell cultures…”Suggests banning all cosmetics with particles <100nmMany sunscreens contain ZnO particles <100 nm
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Nanoparticle Safety
NGO Friends of the Earth issue report requesting ban on all skin care products w/particles <100nmClaim: some nano-articles are dangerous, so ban allIndustry claims some nano-particles are safe, so don’t worryFDA says we only believe data in peer reviewed journals, but form task force to investigate
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LA-950 Data: % Below 100 nm
TiO2
Sunscreen
LA-950 can measure down to nanoparticle range (<100 nm)Plus up to mm rangeIdeal instrument to detect
nanoparticles in presence of larger particles
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No Dilution: Acoustic Spectroscopy
0
1
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7
8
At t
enua
tion
[dB
/cm
/MH
z]
100 101 102
Frequency [MHz]
zinc oxide A in solvent
zinc oxide B in water
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
P SD
, wei
ght b
asis
0
20
40
60
80
100
n ano
-par
ticle
s ran
g e10-2 10-1 100 101
Diameter [um]
zinc oxide Bzinc oxide A
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No Dilution: Acoustic Spectroscopy
0.0
0.2
0.4
0.6
0.8
1.0
1.2PS
D, w
e igh
t bas
is
10-2 10-1 100 101
Diameter [um]
Zinc oxide, reagent ACS by Acros OrganicsZinc oxide, 99.5+% Acros OrganicsZ50-500 USPZ52-500 USPS80249 by Fisher ScientificZinc oxide 99.99% by Alfa AesarZinc oxide ACS MO Biomedicals, LLCPolystormorTM by Mallinckrodt ChemicalsNanopowder America Elements
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No Dilution: Acoustic Spectroscopy
1
2
3
4
5
6
7
% n
ano-
par t
icle
s, m
easu
red
1 2 3 4 5 6% nano-particles, estimated
Percentage of nano particles in Z52-500 sample after incremental additions of the Mallinckrodt Chemicals sample. The X-axis is a percentage calculated from the known amount of the added Mallinckrodt sample, assuming that it contains 20% on nano-particles, according to the Table 1. The Y-axis is a percentage calculated from the attenuation spectra, which is measured for the mixture.
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Nanoparticle or Not?
Details:Silver Powder, 99.9% (metal basis) APS: 30-50 nmSSA: 5-10 m2/gParticle Morphology: sphericalCrystallographic Structure: cubic
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Nanoparticle or Not?
SSA = 6/ρD
50 nm
D from SEM ~50 nmD from SSA ~60-70 nmD from DLS ~250 nmSo: is this a nanoparticle?
ultrasound
Used ultrasound to disperseto primary particles or useweak acid to break bondsD from DLS ~50 nm
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Nanoparticle or Not?Volume vs. Number Distribution
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Nanoparticle or Not?Sample Prep Matters: Ultrasound
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ConclusionsMany techniques can measure <100 nm
DLS when all sample <1 μm– LB-550
Diffraction for below + above– LA-950
Acoustic spectroscopy for undiluted tests
– DT-1201
Beware that choice of techniques, sample prep & report basis influence results
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NanononsenseGrey goo is a hypothetical end-of-the-world scenario involving molecular nanotechnology in which out-of-control self-replicating robots consume all matter on Earth while building more of themselves—a scenario known as ecophagy
Remember Ice-9?