Nanotechnology: Why small?

Science and engineering on length scales approaching molecular dimensions

NSEC(Nanoscale Science and Engineering Center)

Ohio State University

Length scales

≈ 1 meter (1m)

Bats are between 0.81m and 0.86m.

Length scales 109m

Length scales

109m 108m 107m 106m 105m 104m 103m1010m

1nm (nanometer) 1mm (millimeter)1m (micrometer)1Å (Ångström)

1m

glucose

hemoglobin

bacteria (E. coli)

red blood cell

roundworm (C. elegans)

waterO-H bond

images: mine, or lifted from Wikipedia

Nanoparticles

Why small?Nanoparticles for drug delivery

100-200 nm

From Nanotherapeutics, A. Lamprecht, ed. (2009)

antibodies attach to tumors

surface treated for adsorption into cells

Why small?

Nanoparticles for drug delivery

D. Irvine, Nature Materials, 10, p.342 (2011)

Particles that encapsulate chemicals

http://www.fooducation.org/2009/02/my-first-spherification.html

Sodium alginate is a starch from seaweed.

Ca2+ cross-links alginate, forms particles.

CaCl2solution

Particles that encapsulate chemicals

http://www.fooducation.org/2009/02/my-first-spherification.html

Mixtures will contain “deliverable”, like Congo red dye.

CaCl2solution

color change in acid solution

“Not so nano” particles for drug encapsulation

Acid solution is like body of patient.

Dye is like drug to be delivered.

Ferrofluid A ferrofluid is a liquid containing iron oxide “nanomagnets” (10nm diameter).

Ferrofluid

Macro-particles have multiple domains with cancelling magnetization.

Nano-particles form single domain

FerrofluidNano-particles easily oriented by magnetic field

apply magnet

Ferrofluid

N

S

N

S

N

S

N

S

Gold and silver nanoparticles

Gold is the color “gold”,and silver is the color “silver”…

…except for gold and silver nanoparticles.

Gold nanoparticles

nanoparticle diameterTransmission electron micrograph of 18nm colloidal gold particles prepared by citrate reduction.

Image by Daryl Meyerwww.ansci.wisc.edu/facstaff/Faculty/pages/albrecht/albrecht_web/Programs/microscopy/gallery.html

Image by Irawati Kandelawww.ansci.wisc.edu/facstaff/Faculty/pages/albrecht/albrecht_web/Programs/microscopy/colloid.html

Gold nanoparticles in First Response pregnancy test

human chorionic gonadotropin (hCG)

Why small? Cell sorting with magnetic particles

T-cell

Beads coated with anti-CD3/CD28 antibodies

Cell sorting with magnetic particles

Trapping Magnets

NS N S

Cell sorting with magnetic particles

Cell sorting with magnetic particles

voice recognition

Next step: single-cell analysis

Cells are encapsulated in small droplets for individual analysis.

Single cell injection: detection of cancer cell

DyeQuencherMolecular beacon lights up when it finds target

Movie of molecular beacon finding target DNA after injection in cancer cell.

Nanochannels

Surface to volume ratio

0.3nm

amorphous SiO2 (a.k.a. “glass”)water

“nanochannels” < 10nm : most fluidin contact with surface.

Surfaces and volumes in“Measuring the visible to understand the invisible”

Why small?Fast, accurate, affordable, diagnostics

Point-of-care-testing (POCT)available now for glucose, INR (clotting),…

in the future• cardiac ischemia (lack of oxygen),

before necrosis (death of heart muscle)• indicators for breast cancer, prostate

cancer, …• circulating tumor cells (CTCs)

Implants• real-time information on blood flow• monitor glucose, INR, … and dispense

medication

Why small?Fast, accurate, affordable, diagnostics

Point-of-care-testing (POCT)

Current medical practice: imaging, remote testing

Imaging – MRI, mammogram (X-ray), microscopic analysis of biopsies …• not amenable to POCT• disease not always detected in earliest

stage

V. Andolina, Mammographic Imaging, 2nd Ed. (2001)

Pathology lab• slower• more sample needed

“Lab on a chip”

Miniaturization• Enables POCT and implants• both challenge and opportunity

Advantages of miniaturization• less sample: finger prick, not blood draw• rapid analysis• many tests at once• molecules have more contact with surface

Why small? Integrated blood barcode chipHeath and co-workers: J.Amer.Chem.Soc. 129:1960 (2007), Nature Biotech. 26:1373 (2008)

bar width = 20 m (fine human hair)

1pM means one protein for every 55000000000000 water molecules

Nanofibers

Nanofiber treated fabric

polyester nanofibers(400nm diameter)

Lotus leaf is nature’s water-repellant “fabric”

10m

Electrospun nanofibers

St. Charles Preparatory High School

Electrospun nanofibers

Aligned vs. non-aligned nanofibers

Electrospun collagen type I nanofibers. (A) stationary target, (B) aligned nanofibers when electrospinning was performed using a rotating drum (7 m/s).

10 μm10 μm

Nöth, Rackwitz, Steinert, Tuan Advanced Drug Delivery Reviews 62:765 (2010)

Nanofiber scaffolds for tissue engineering

Li, Tuan Current Protocols in Cell Biology 25:2 (2009)

electrospun poly(l-lactic) acid (PLLA) nanofibrous scaffold seeded with chondrocytes for cartilage tissue engineering

“Nanotechnology in Vascular Tissue Engineering”

Carbon nanotubules

“Molecular Modeling”

Schedule

Preview of Nanotech West Tour

NSEC(Nanoscale Science and Engineering Center)

Ohio State University

Micro-milling and femtosecond laser

Metro High School tour of Nanotech West

Construct micro- and nano-structures for biomedical devices

Micro-milled structures for blood cell separation

25 “tree” of 400m micro-milled structures in polycarbonate.

Laurell, Petersson, Nilsson Chem. Soc. Rev., 36:492 (2007)

Femtosecond laser ablation

laser ablation of fused quartz. channel profiles for three samples.

Farson, Choi, Zimmerman, Steach, Chalmers, Olesik, Lee, J. Micromech. Microeng. 18:035020 (2008).

Integrated blood barcode chipHeath and co-workers: J.Amer.Chem.Soc. 129:1960 (2007), Nature Biotech. 26:1373 (2008)

bar width = 20 m (fine human hair)

1pM means one protein for every 55000000000000 water molecules

DNA

images:wfrhs.wcpss.net/teched/biotech.html; Lodish, Molecular Cell Biology

0.34nm

1.0nm

DNA

T A

C G

TA

CG

DNA hybridization

A

G

T

C

T

C

A

G

single-stranded DNA single-stranded DNA

complimentary

anti-sense

DNA hybridization

T

C

T

C

A

G

A

G

double-stranded DNA

Integrated blood barcode chipHeath and co-workers:J.Amer.Chem.Soc. 129:1960 (2007)Nature Biotech. 26:1373 (2008)

aminated surface binds DNA

DNA with different sequences printed onto 20m strips

complimentary

antibodies to target biomarkers

Integrated blood barcode chipHeath and co-workers:J.Amer.Chem.Soc. 129:1960 (2007)Nature Biotech. 26:1373 (2008)

aminated surface binds DNA

DNA with different sequences printed onto 20m strips

Integrated blood barcode chip

aminated surface binds DNA

hybridized double stranded DNA

antibodies to target biomarkers

biomarkers from blood sample

Integrated blood barcode chip

aminated surface binds DNA

hybridized double stranded DNA

antibodies to target biomarkers

biomarkers

antibodies with fluorescent label

Further challenge: “active” manipulation of fluid, cells

Blood barcode ship is miniaturized version of currently available labs tests.

www.biology.arizona.edu/immunology/activities/elisa/elisa_intro.html

More active control of fluid and cells• injection into, or sampling cells• more complex lab on a chips for biomarker detection• cell sorting, single-cell analysis• blood testing or drug dispensing implants

Fluid flow is “passive” – (capillary action, Zweifach-Fung effect)

Beyond pumps: electroosmotic flow

dye

++++

battery

flow

Electroosmotic flow (EOF) visualized with fluorescent dye

images furnished by Derek Hansford

Nanonozzle array

++

+

+

+

+voltage

nanonozzle for biomolecule delivery

Wang, Zeng, Lai, Juang, Yang, Lee Adv.Mat.17:1182 (2005)

Polymer nozzle lined with amorphous silica (“glass”).

Model electroosmotic flow in silica nanonozzleOSU NSEC

“glass” (SiO2)

salt water (like blood plasma, cell fluids)

Model electroosmotic flow in silica nanonozzleOSU NSEC

voltage

Glass surface has negative electrical charge, fluid has positive charge. Si

O

“ion” = atom or molecule with positive or negative charge

+

+

++

+

glass

+

++ +

water

extra

salt

Electroosmotic flow

+ ion

ion

solvent

Zhu, Singer, Zheng, Conlisk, Phys. Rev. E71(4): 041501 (2005).

negatively charged wall

+++++++++++++

biomarkers, cells

Cell sorting using electroosmotic flow

Scherer, Quake and co-workers, Nature Biotech. 17:1109 (1999)

Target cells labeled with light-sensitive probe.

Light detector senses target cells.

When target detected, electroosmotic flow used to reverse flow direction by reversing voltage.

input

waste

collection

Photolithography

Metro High School tour of Nanotech West

Photolithography

silicon

oxide (SiO2)photoresist

optical mask

light

Photolithography

silicon

oxide (SiO2)photoresist

optical mask

light

Photolithography

silicon

oxide (SiO2)photoresist

etch oxideremove remaining photoresist

Biomedical devices made with photolithography

http://www.4m-association.org/book/export/html/123

micro-mixer manufacture disk-shaped nano-particles.

Andriani et al., Biomaterials 33:5504 (2012)