Replacing the function of failed biological tissue
- and A technology push in the direction of biomedicine at the molecular scale
J.N. Randall, Jim Von Ehr, Josh Ballard, James Owen, Udi
Fuchs, Rahul Saini, and Sergiy Pryadkin
Zyvex Labs
Richardson, Texas
jrandall@zyvexlabs.com
What’s Zyvex?
Zyvex Corporation 1997 – 2007
– Zyvex Instruments – Richardson Texas
• Nanoprobing tools – Acquired by DCG Systems 2010
– Zyvex Technologies – Columbus Ohio
• Carbon Nanotube / Polymer Composites
– ZyCraft – a Global Company
• Independent Unmanned Surface Vehicles
– Zyvex Labs – Richardson Texas
• Atomically Precise Manufacturing
• Healing the Blind
History of Commercializing Nanotech
• Zyvex Technologies has developed the world’s leading CNT
enhanced composites:
• Zyvex Instruments has developed the world’s leading
nanoprobing technology:
• Zyvex Labs is developing Atomically Precise Manufacturing:
3nm
3nm
3nm
Nano Retina
Innovative Sight Restoration
John N. Randall
Nano Retina Executive Vice President
4
Causes of Blindness in the US
67% possibly treatable by Nano Retina
5
Worldwide Artificial Retina Market
Worldwide blind
persons
New blind persons
(annually)
15,000
implants
>6M
>200,000
> $1B
sales
Limited treatments currently available
6
Second Sight’s Argus II
• 4-8 hour surgery
• Wires come in and out of the sclera
• Electrodes sit at the surface of the retina
Limited spatial resolution
at retina surface
Surface electrode excites nerve bundles
Nano Retina advantages
• 600 penetrating electrodes stimulate bipolar
region.
• Normal optics of the eye are used (no camera)
• Power is delivered by IR laser through the pupil.
• Tiny package is implanted in 30 minutes, with
local anesthetic, on an outpatient basis.
Operation Principles
1. External image received by Bio
Retina thru the eye’s optics.
2. Bio Retina converts the image to
neuron stimulation.
3. Bio Retina stimulates the retinal
neurons connected to the brain.
Bio Retina
implant
5
3
2
IR laser
beam
4
Retina
1
4. Ordinary looking eyeglasses
hold the laser power source.
5. Invisible infrared laser powers
the Bio Retina wirelessly.
 Benefits:

Light and long lasting

Simple implantation

Uses the eye’s optics
10
Bio Retina Functional Blocks
Imager
Analog processing
Neuron Stimulators
Electrodes
ANR1 VLSI
 576 pixels
 Ultra low power
X 100,000 =
 Proven miniaturization
11
Packaging Concept
Record Multi-Electrode Array
 Dense feedthrough array
 676 penetrating
electrodes
 In-vivo demonstrated
Dense package
 Sealed &
Durable
 Biocompatible
 3.5 X 4.5 mm
12
Eyeglasses concept
Battery
Control unit
Dichroic reflector
Prism
Collimator
Laser diode
• Normal vision &
IR implant powering
• Integrated structure
• Battery included
• Eye safe
13
In-Vivo Initial Study
Outcomes
Study approach
 Implantation procedure
development
 30-min surgery technique
 Six-week chronic study of pigs
 No adverse effects
Implantation
Extraction
 Desirable implant adhesion
Histology
14
Sight Resolution
 Resolution is a key performance parameter
 Argus II resolution is 20/1260 only with black and white pixels (6x10)
 Bio Retina I targets 576 pixels possibly providing 20/260 functional vision
 Bio Retina II aims for 20/20 gray scale vision enabling facial recognition
?
20/1260
20/260
20/20
Ambulatory
Functional
Vision -
Vision –
Follow line
Watch TV
Argus I
Argus II
BRI I
BRI II
15
Restoring Sight to the Blind
Bio Retina
6M patients
waiting
An artificial retina
Tiny implant
Accomplished
international
team
Minimally invasive
Functional vision
Prototype
demonstrated in
animal studies
Strong IP
position
Human clinical
trials in 2016
16
The Company
The Team
Founders
Yossi Gross,
Rainbow
Medical CTO
Alon Harris,
Indiana
University
Jim R. Von Ehr,
Zyvex labs CEO
Efi Cohen-Arazi,
Rainbow Medical
CEO
Advisors
Prof. Yael
Hanein, VP
Barbara Marie
Wirostko, Utah
University
Jeffery Grossman
VP Business
Development
Dov Weinberger,
Rabin Medical
Center
Shelley Fried, Richard B. Rosen,
Harvard Medical
NY Eye & Ear
School
Infirmary
Laura Ben Haim
Ophthalmology
researcher
Ra’anan Gefen
Managing director
John Randall
Executive VP
Raul Saini
Mechanical
director
Tuvia Liran
VLSI director
Leonid Yanovitch
Lab engineer
Dorit Raz Prag
Preclinical
director
1910 to 2010
How did we go from horse carriages, manually operated
telephone exchanges, and life expectancy of 50 to space
tourism, gps cell phones, and life expectancy of 80 in only
100 years?
Manufacturing Precision improved
100,000-fold in past 100 years
Norio Taniguchi’s Chart on Machining Precision
Machining
Accuracy
0.1mm
0.01mm
x
x
1mm
x
0.1mm
x
0.01mm
o
x
1nm
Atomic
Distance
1900
1920
1940
1960 1980
2000
1961 Fairchild
Integrated Circuit
Technology nodes in ICs
Manufacturing Precision improved
100,000-fold in past 100 years
Norio Taniguchi’s Chart on Machining Precision
Machining
Accuracy
0.1mm
0.01mm
x
x
1mm
x
0.1mm
x
0.01mm
o
x
1nm
Atomic
Distance
1900
1920
1940
1960 1980
2000
Absolute Precision Manufacturing
• Atomic Precision: +/- one atom
• Absolute precision: No variation
– Everything is exactly the same size
Atom-by-Atom Manipulation
Richard Feynman – “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” - 1959
“STM” – Nobel Prize in Physics 1986
Don Eigler spells out IBM in atoms 1989
Our Goal: Reliable Versatile
Atom-by-Atom Manufacturing
Atomically Precise
Manufacturing
Consortium
Committed to bringing
atom-by-atom manufacturing tools to market
Universities:
Industry:
International Collaborators:
University of Texas at Dallas
Bob Wallace, Yves Chabal,
KJ Cho, JF Veyan,
Zyvex Labs
J. Randall, J. Von Ehr, J. Ballard,
R.Saini, J. Owen, Udi Fuchs
S. Manning
Univ. New South Wales
Michelle Simmons
Wolfgang Klesse
University of Illinois at UC
Joe Lyding
University of North Texas
Rick Reidy, Maia Bischof,
David Jaeger
Colorado School of Mines
Brian Gorman
University of Texas at Austin
S. V. Sreenivasan
State Agency:
North Texas RCIC
Maria Smith
IC Scanning Probe Instruments
Neil Sarkar
Molecular Imprints Inc.
S. V. Sreenivasan
University College London
David Bowler
University of Nottingham
Prof. Moriarty
Richard Woolley
Tiptek Inc.
Scott Lockledge
Nanoretina
Raanan Gefen
National Labs:
NIST
Rick Silver, Jason Gorman
Future Collaborators:
Your Institution
Your name here
Making AXA Manufacturing a Reality
Developing a system from the
ground up for complete freedom –
not force-fitting off-the-shelf systems
UHV STM System
Vibration Isolation
Software system with growing capabilities
• 2 Lyding Scanners
• Field Ion Microscope
• Closed loop heating
• In-situ tip & sample prep
• Automated dosing
• Custom control system
• Custom software
• Remote operation
• Two Systems Fully
Operational
Material System:
Si(100)2x1-H
STM Image of Si(100)2x1-H
Dimer rows spaced
0.77nm apart.
Dimer rows switch
direction with each
atomic layer.
This surface has been
highly studied, making
studies easier to
understand.
12 nm
Details: Crystal Silicon Surface
– Pixels formed from 2 dimers
Depiction of Surface of “Si (100) 2x1”
•
Each surface atom has 1 unfilled bond:
–
–
•
•
When bare, the atom is reactive
With H there, the atom is “passive”
Two atoms form one surface dimer.
We define one pixel as two adjacent
dimers
Identifying Pixels on Si Surface
Fourier analysis allows us to identify
the pixels on the Si surface.
We can associate a design grid with
the Si lattice, and use the lattice as a
global fiducial grid.
AP H depassivation
with STM
Hersam and Lyding UIUC
3nm
Zyvex Labs
Using, creep and drift correction and alignment
to the lattice, more accurate litho is possible.
Theory
Experiment
Atomic precision pattern placement over small area.
Have currently extended to roughly 40x40nm area.
Automated Vector Compiler
How to do Hello Kitty
Optimize Write Distances
Determine all possible vectors
Subtract longest vector from pattern
Perform Litho
Input Vector List
(Find pixel info)
Write vectors
Step in scan mode
#1 DR saturated
#1 DR unsaturated
(126, 133, 208, 133)
(126, 132, 208, 132)
(126, 131, 208, 131)
(126, 130, 208, 130)
(126, 129, 208, 129)
(122, 129, 122, 153)
(121, 129, 121, 153)
(120, 129, 120, 153)
(67, 160, 100, 160)
(67, 161, 100, 161)
(67, 162, 100, 162)
(67, 163, 100, 163)
(67, 164, 100, 164)
(67, 165, 100, 165)
(67, 166, 100, 166)
(67, 167, 100, 167)
(100, 133, 100, 168)
(67, 133, 100, 133)
(67, 133, 67, 168)
(67, 168, 100, 168)
Optimize Step Distances
Put longest vector in master vector list
Find vector with nearest start or end
point to end of previous vector
Remove vector from search list
Patterned Epitaxy
Litho
Litho
Litho
Litho
Litho
Owen et al. J. Vac. Sci. Technol. B 29 06F201 (2011) DOI: 10.1116/1.3628673
Atom-by-Atom Manufacturing
2 nm epitaxial growth, automated, overnight
process with system cycling through:
•
Imaging
•
Litho
•
Depo
New Device Regime!
Simmons has shown high-precision 2D placement of
dopants in silicon leads to remarkable devices
• Insulating, semiconducting, and metallic regions created in
single crystal silicon
• A new device regime with:
NO Metal Oxide Semiconductor interface
Pattern Transfer
ALD of metal oxide
H H H
H H H H
Zyvex Labs
Metal
precursor
H2O
H H H
H H H H
MO2
UT Dallas
RIE
NIST
Hard Etch Masks
AFM of Patterns after ALD
Linewidth
Dependence of RIE
a
b
c
100
nm
d
-50
Linewidth (nm)
50
HDL
ALD
RIE
0
x (nm)
50
e
40
30
ALD
ALD'
HDL
RIE
20
10
0
1
2
3
4
5
6
Line Number
Lines written with FE mode litho can easily be controlled down to 10 nm, but
edges matter
Sharpened edges
patterns
b
a
59
52
46
40.7 nm
34
28
16
12
0
Closeups of NI
Case Study:
Master Nanoimprint Templates
AP Structures
Products
• Molecular binding sites
• Nanopore membranes
• Catalysts
• Nanooptical elements
• NOT VLSI
Polymer
Some loss of fidelity:
• From Si structure to template
• From Master to Daughter
• Imprint Process
• Pattern Transfer
Case Study: Nano Mechanics
MEMS Oscillators are orders of
magnitude better than electronic
oscillators in terms of their quality factor
and produce much better filters.
BUT semiconductor processing has
terrible relative precision making the
control of frequency poor.
Atom by atom manufacturing would produce
•
•
•
•
An oscillator with a near terahertz frequency
Excellent control over frequency
Extremely high Q
Myriad applications such as ultra low power radios and extremely
sensitive sensors
Nano Bio Uses
• Structures that interact in extremely precise ways with
specific molecules:
– Ultra precise molecular filtering
– Precisely designed binding sites for ultra effective drugs to
enhance or block protein action
– Designed enzymes
Case Study: DNA “Nanopore” for
Ultra-High-Speed DNA Sequencing
DNA readout mechanisms are
extremely sensitive to distance
• Currently far too much variation
Game Changer: AXA
Manufactured “Nanopore” DNA
Sequencers
• Atomic precision will enable
speeds needed for ultra low cost
• True “personalized medicine” and
tailored treatments – a medical
revolution
• Optimized crops
• Rapid identification of evolving
diseases
Concept:
Molecular Specific Filtering
Molecule A
passes through
pores in membrane
Molecule B can not
pass through
pores in membrane
The ability to control a molecules ability to pass through the filter
Can be based on shape of the pore as well as the size
And possibly the surface chemistry of the membrane and pores
Selective Depassivation
R = SH, NO2, NH2, CH3, COOH, etc.
OH
OH
CH3
Investigate Bio molecular
Interactions
Distance selectable
With atomic resolution
OH
CH3
Cell – Surface interaction
• Cell’s interactions with
different surface textures are
well documented.
• We could make surfaces (via
nanoimprint templates) with
unprecedented precision,
designed for specific
molecular interaction with
specific molecular structures
on cell surfaces.
We are looking for collaborators
jrandall@zyvexlabs.com
Thank You