Biomaterials, the Nanobiointerface, and Surface

Biomaterials, the Nanobiointerface,
and Surface Modification Strategies
Buddy D. Ratner
University of Washington Engineered Biomaterials (UWEB),
Department of Bioengineering,
Department of Chemical Engineering,
University of Washington,
[email protected]
An NSF Engineering Research Center
Nanotechnology (and nanoscience) continue to grow in prominence
Where did nano/bio ideas come from?
How are they relevant to biocompatibility?
How can we use nano ideas for biomaterials?
Biointerface and biosurface
The roots
roots of
of nanotechnology:
nanotechnology:
The
1770
Ben Franklin
1890
Agnes Pockels
1920
Irving Langmuir / Katherine Blodgett
1940+
Pauling / Watson & Crick
1959
Richard Feynman
1970
Helmut Ringsdorf
1986
Binnig and Rohrer
2000
Bill Clinton
Modern nano ideas
The principles of physics, as far as I can see,
do not speak against the possibility of
maneuvering things atom by atom. It is not an
attempt to violate any laws…
Richard Feynman, 1959
What went on in the
intervening years?
Imagine the possibilities…
Bill Clinton, CalTech, 2000
The principles of physics, as far as I can see,
do not speak against the possibility of
maneuvering things atom by atom. It is not an
attempt to violate any laws…
Richard Feynman, 1959
The molecular biologists and molecular bioengineers have been busy!
(1960s - 2000)
Imagine the possibilities…
Bill Clinton, CalTech, 2000
Rube Goldberg Simplified Pencil Sharpener
Open window (A) and fly kite (B). String (C) lifts small door (D) allowing moths (E) to escape and eat red flannel shirt (F).
As weight of shirt becomes less, shoe (G) steps on switch (H) which heats electric iron (I) and burns hole in pants (J).
Smoke (K) enters hole in tree (L), smoking out opossum (M) which jumps into basket (N), pulling rope (O)
and lifting cage (P), allowing woodpecker (Q) to chew wood from pencil (R), exposing lead. Emergency knife (S)
is always handy in case opossum or the woodpecker gets sick and can't work.
Biological Triggers of Cell Functions
hormone
(more than 1000 such G protein
receptors have been identified)
Adenylyl
Cyclase
G protein receptor
cell membrane
hormone binding triggers
conformational change
cytosol
G protein
activated
G protein
ATP
cAMP
an important second messenger
Nature:
the ultimate
nanoengineer
Soong, et al. Science, 290, 1555 (2000)
Schematic diagram of the F1-ATPase biomolecular motor-powered nanomechanical device. The
device consisted of (A) a Ni post (height 200 nm, diameter 80 nm), (B) the F1-ATPase biomolecular
motor, and (C) a nanopropeller (length 750 to 1400 nm, diameter 150 nm). The device (D) was
assembled using sequential additions of individual components and differential attachment chemistries.
Ned Seeman - DNA architechures
Artist’s
conception
Marlaria protozoa
invade red cells
in a similar manner
“Rules” common to nanotechnology and molecular biology
• “Bottom up” fabrication (molecules up)
• self assembly
• supramolecular structure
• self replication (J. Rebek, etc)
• a new applied physics
- quantum tunneling
- diffusions and flows
• integrated use of soft and hard matter
• engineering with kT noise
• surface science principles
• hydrophobicity / interfacial properties
Scaling relationships - nano to macro
µm flow
Protein
DNA
20µm
10-9 m
10-9 m
- 10-5 m
20µm
Uncoated
Coated
10-5
10 m
Implant device
Array device
Nanogen
10-5 m - 10-2 m
10-2 m
So, how does “nano” connect to “macro-biomaterials?”
Coat the device
with a
nanometerdimension film.
Coat the device
with proteins.
USING NANO CONCEPTS IN
DESIGNING BIOMATERIALS
Introduction to modern biomaterials -How can nanotechnology help?
Surfaces of biomaterials
In 50 years since the first biomaterials (as we know them today) were
developed, the field has evolved into a $100 billion endeavor that
saves lives and improves the quality of life for millions.
B-17
Common Medical Implants
Finger joint
Breast implant
Heart valve
CNN
Hip joint
Artificial heart
http://www.usc.edu/dept/biomed/
bme490.981/artificial_heart.htm
Intraocular lens (IOL)
Success in Biomaterials
after ~50 years of research and development:
W
O
R
L
D
W
I
D
E
• IOLs (>7,000,000/yr) (PMMA, silicone)
• Hip and knee Prostheses (>600,000/yr) (titanium, steel, PE)
• Vascular Grafts (>300,000/yr) (Teflon, Dacron)
• Heart Valves (>200,000/yr) (carbon, fixed tissue)
• Percutaneous Devices (>100,000/yr) (titanium, silicone)
• Stimulatory Electrodes (>100,000/yr)(platinum, iridium)
• Catheters (millions/yr)(silicone, PVC, PEU, Teflon)
• Stents (>2,500,000/yr)(stainless steel)
U.S. healthcare market (1998) > $1 trillion
Millions of lives saved / The quality of life improved for millions more
how well do biomaterials really work?
• IOLs (25%-50% reoperation rate)
• Hip and knee Prostheses (still a 10-15 yr lifetime)
• Vascular Grafts (no healing)
• Heart Valves (calcification or thrombosis)
• Percutaneous Devices (no seal)
• Stimulatory Electrodes (electrode encapsulation)
• Catheters (thrombosis, infection; 1,000’s of deaths/yr)
• Stents (clotting and closure)
• Contact lenses (discomfort and eye injury)
• Dental Implants (loosening)
Problems of much concern, but also,
An opportunity…
Why the complication rate?
What can we do about it?
A central premise of the biomaterials field has been:
The surface dictates the biological reaction
BIOMATERIAL
How does the surface dictate healing?
Biocompatible Biomaterials Healing: Encapsulation and Isolation
1.
8.
Biomaterial
injury
The biomaterial is
encapulated and
isolated
Biomaterial
Biomaterial
2.
protein
adsorption neutrophil
fibronectin laminin
GAG
TSP?
SPARC?
ECM: collagen
Biomaterial
7.
3.
cell interrogation
fibroblast
monocyte /
macrophage
4.
release
In conjunction with ECM molecules...
6.
Communication to
fibroblasts
release
Growth and attachment inhibitors and stimulators
PDGF
FGF
interleukins
TGF or
EGF
TNF
5.
Giant cell formation at the
Implant surface -- frustrated
phagocytosis
SEM of tissue surrounding subcutaneous device
in rat: 6 weeks after implant
PTFE
device
loose connective tissue-
From K. Ward, Isense Corp
dense foreign
body capsule
e
th n
k eo
s
a rg
su
An operational definition of
“biocompatibility“
The foreign body reaction
no adhesion between
implant and the capsule
circa, 2001
thin walled
capsule
Ti
PET
PEU
Implant
C
PLA
PDMS
PE
f
f
o
ed body
l
l
Wa the
m
fro
The implant, after approximately 1 month, is found
within a thin, relatively acellular, collagenous sac.
The reaction site is quiescent.
What is the similarity between all these widely different materials?
Ti
PDMS
PEU
PET
C
PLA
PE
They all have uncontrolled
interfacial proteins!
• HYPOTHESIS •
Can we conclude that surface
properties do not matter?
Not a good conclusion:
• Biology uses surfaces and interfaces, too.
• All in vitro biomaterials directly exploit surfaces
Nature does it’s work at interfaces and surfaces:
e
c
a
Lipid membrane
f
ur
s
e
ul
(Proteins
Sugars
Water)
cell
ec
l
o
m
Collagen
and other
extracellular
matrix proteins
Medical device
(biomaterial)
(the molecules assemble
to form a surface)
www.cellsalive.com
http://cellbio.utmb.edu/cellbio/membrane_intro.htm#Architecture
Biology’s Surface Tricks
1. Complexity
2. Recognition
•
•
•
•
enzyme-substrate
antibody-antigen
DNA-RNA-protein
lectin-carbohydrate
3. Assembly (order)
• collagen
• cell wall
• supramolecular structure
4. Mobility
5. Optical sense
Surface Modification:
the rationale
surface
Unchanged:
bulk
- mechanical properties
- configuration
- surgeon handling characteristics
- manufacture
Only alter the surface zone to influence:
biocompatibility
other performance parameters
Surface Modification Methods
• Plasma treatment and deposition
• radiation grafting
• chemical reaction of the surface
• ozonolysis
• photoreaction
• ion implantation
• ion etching
• solvent cast films
• surface active modifiers (low and high MW)
• metalization
• self assembly
• micro-contact printing
• immobilization of biomolecules
UWEB
How biomaterials
heal now!
Biomaterial
The foreign body reaction
Biomaterials healing
in the future
Biomaterial
A reconstruction of the anatomy!
Normal wounds heal this way.
Why not our biomaterials?
University of Washington Engineered Biomaterials (UWEB)
UWEB Vision Statement
...
... to
to evolve
evolve engineered
engineered biomaterials
biomaterials that,
that,
by
by emulating
emulating nature’s
nature’s own
own mechanisms,
mechanisms,
control
control with
with precision
precision the
the interaction
interaction of
of
biology
biology with
with synthetic
synthetic materials.
materials. This
This leads
leads to:
to:
•• biomaterials
biomaterials that
that heal
heal and/or
and/or function
function in
in an
an improved
improved manner
manner
•• improved
improved diagnostics
diagnostics
•• aa new
new intellectual
intellectual frontier
frontier as
as aa platform
platform for
for our
our educational
educational and
and
outreach
outreach efforts.
efforts.
Can mechanistic biology be
reduced to a clockwork model
(the province of the engineer)?
an NSF Engineering Research Center
University of Washington
Engineered Biomaterials (UWEB)
research
team effort
industry
education
UWEB is…
• Biomaterials that heal (engineered biomaterials)
• Improved diagnostics
20 professors and 100 students focused on biology at surfaces
twenty six companies in partnership to advance biomaterials
a focused effort to bring more students, and more diverse
students, into engineering and science
So how can we get around this foreign body reaction?
The Central UWEB Strategy
•stealth materials and non-fouling materials
Use where necessary
•Prevent non-specific interactions
Always!
•Encourage specific interaction
Engineered surfaces
An Engineered Biomaterial
• the biology is well understood (the correct receptor
interaction)
• molecules in defined orientation, conformation stabilized
• bland, non-interactive regions between receptors?
(pattern the surface chemistry)
10 nm
Medical device
A focus on the interface:
The Basic Repertoire of Surface Analysis Methods
x-rays
. . .
.
.
... electrons
primary
ions
+
+
+
ESCA
SIMS
.. .. ..-secondary
.. ions
+
Macintosh II
Macintosh II
laser
AFM
detector
θ
lever
Macintosh II
Contact angle
H
T
AL
E
ST
A strategy for non-fouling (stealth) surfaces
Poly(ethylene glycol) or Poly(ethylene oxide) (PEO)
(O-CH2CH2)n
PEO surfaces are found to
resist protein and cell pickup
Our monomers are glymes, e.g. tetraglyme: CH3 (O-CH2CH2)4 O-CH3
A 20 nm coating
Advantages of Plasma Deposits
•
•
•
•
•
•
•
•
•
•
•
dry processing
rapid
pin-hole free
conformal
can be done on continuous basis
tenacious adhesion to the substrate
many possible chemistries
many possible substrates
monomer costs are negligible
sterile product
much precendent
Plasmas -- Unique Monomers and Unique Surface Chemistries
Thin film deposition
“Monomer”
Methane
Tetrafluorethylene
Benzene
Methanol
Ethylene oxide
Tetraglyme
Acrylic acid
Allylamine
Hydroxyethyl methacrylate
N-vinyl pyrrolidone
mercaptoethanol
Film Characteristics
Hydrocarbon, diamond
Fluoro, hydrophobic
graphitic
polar
Rigid, polar
Non-fouling
-COOH-rich
Amine-rich
Hydrogel, hydroxyl
hydrogel
Sulfur-containing
H
Fibrinogen Adsorption to
Plasma Polymerized Tetraglyme on FEP
T
AL
E
ST
Absorbed Fbgn (ng/cm
2
)
160
140
UWEB
116
120
100
80
60
Teflon
control
Various glyme coatings
40
20
0
0
A
1.6
3.7
6.3
6.4
B
C
D
E A (EtOH)FEP
0
Data of T. Horbett, V. Pan and B. Ratner
Pseudomonas aeruginosa attachment and growth
Growth Mode: Net Accumulation of colony forming units (CFU)
160
140
Glass
Glymes
Cyclics
120
% change
in number
of CFU
100
80
60
40
20
0
Gls 1 Gls 2
Mono 1 Tri 1 Tri 2 Tetra Tetra Diox 12cr4 15cr5 15cr5
5w 20w
5w 20w
Data of E. Johnston, J. Bryers and B. Ratner
Photopatterning of RFGD Films
UV
Cast
Expose
Develop
UV
Re-expose
Analyze
Re-develop
Polymerize
Methylobacterium extorquens AM on patterned tetraglyme
Upon seeding
70 hrs. later
Data of Yael Hanein, Karl Boehringer, Vickie Pan and Buddy Ratner
Methylobacterium extorquens AM on patterned tetraglyme
0
70 hrs.
Images taken every 2 hrs.
Data of Yael Hanein, Karl Boehringer, Vickie Pan and Buddy Ratner
2
Monocyte Density (cells/mm )
Monocyte adhesion to plasma
polymerized tetraglyme
2000
R2=0.983
1500
1000
500 5, 10, 20 W
0
0
50
100
40, 60, 80 W; FEP
150
200
250
300
350
400
Adsorbed Fibrinogen (ng/cm2)
Mingchao Shen, et al.
Histology of tissues surrounding implants
Tetraglyme
Implant
FEP
Implant
60
50
Fibrous
40
Capsule
30
Thickness
(um)20
10
0
FEP
Tetraglyme
Skin side
Muscle side
Collagenous Tissues
M. Shen, et al.
Conclusion
We believe non-fouling surfaces to be necessary,
but not sufficient, for biomaterials that heal.
UWEB
The Clues to Healing
Materials that “heal” without
a capsule...
Hydroxyapatite (bone)
5 µm porous structures
fine fibers
Kukobo Titanium (bone)
Tyrosine polycarbonate?
RGD peptides?
Molecules always present
in healing wound sites
SPARC
Osteopontin
Thrombospondin
Fibronectin
Fibrinogen
Laminin V
UWEB “Rosetta Stones” -- read the code and learn how nature heals!
5 µm pores
Made by
microsphere
templating
(A. Marshall)
Porous materials have been examined for toxicology and endotoxin
Crystalline surface of packed 60µm beads
(oblique view)
Porous pHEMA templated with a
crystalline array of 60µm beads
Electrospinning of fibro-porous materials
“skinny fibers”
Capsule Thickness µm
(mm)
55
45
35
25
15
5
-5
0
5
10
15
20
25
FiberDiameter(mm)µm
Joan Sanders, et al.
Turn on specific reactions
Matricellular Proteins
ECM
SPARC
Tenacin
Osteopontin
Thrombospondin
Cells
Osteopontin coating is a normal part of implant
healing: ePTFE subcutaneous implants
7 days
28 days
Osteopontin stains brownish-red
Giachelli, et al.
Osteopontin-Immobilized PolyHEMA
(Lysine-Immobilized control)
50 m
50 m
Lysine-Immobilized PolyHEMA, explanted
after 28 days
OPN-Immobilized PolyHEMA, explanted
after 28 days
BV Score = 1
BV Score = 3
Data of Stephanie Martin, Cecelia Giachelli and Buddy Ratner
Vascular density and capsule thickness
of foreign body capsules in control and TSP2-null mice
(4 week implantation)
genotype
Thrombospondin
normal mice
Thbs2+/+
Thrombospondin
knockout mice
material
vessels/capsule
Capsule thickness facing
dermis (µm)
body wall (µm)
PDMS
10±10
55±8
24±3
Ox-PDMS
12±8
58±7
25±4
PDMS
100±20
91±7
36±5
Ox-PDMS
90±14
95±8
38±5
Thbs2-/-
Data of Kyriakides, Leach, Hoffman, Ratner and Bornstein
Proc. Natl. Acad. Sci. USA 96, 4449-4454.
How can we deliver these “healing”
signals on real world medical devices?
Molecular templating is a possibility...
Proteins on mica
CH 2O
H
O
Coat with sugar
Deposit plasma film
Glue to glass
O
H
H
O
O
O
H
HOC
H2
O
H
O
O
H
O
H
CF3 CF CF2
CF CF CF2
CF CF CF
CF2 C
CF3
CF2 CF CF
Peel off mica/
dissolve proteins
Do the pits recognize
the template protein?
Galen Shi, et al.
Nature, 398, 593-597(1999)
A hypothesis for the recognition mechanism
Imprinted Binding Pocket
CHO
O
H
HOC
O
CH 2
O
O
OH
HO
OH
O
OH
HO
HO
OH
O
OH
H
H
OH
H
N
HOCH
O
OH
Ser
O
OH
HO
O
OH
O
Lys
Glu
Template Protein
O
HO
O
OH
N
CH
OH
H
N
His
Tyr
HO
OH O
H
O
H
O
CH
HO
O
H
N
Asn
Examples illustrating the fidelity of the imprint to reproduce the template
template
TEM image of the imprint
AFM
3 nm
1 m
E. coli
Glutamine Synthetase
(MW 600 KD)
14 nm
20 nm
E. coli
1 m
Distribution (%)
imprint
20
15
10
5
0
5
10
15
Diameter (nm)
20
Surface Topography (AFM) of Protein Imprints
45 nm
4 nm
6.5 nm
14 nm
5 nm
3 nm
Albumin
Fibrinogen
(MW 66 KD)
(MW 340 KD)
0
20 nm
0
20 nm
200
200
0
0
400
200
400
BSA IMP
600 nm
400
200
Fbgn IMP
400
600 nm
Microcontact printing (µCP)
silicon
coat with
resist and expose
Silicon
resist
Silicon
Silicon
PDMS
Silicon
PDMS
develop resist
Silicon
PDMS
etch
Silicon
PDMS
strip
Silicon
silanize
coat with
PDMS
strip from
silicon
ink the stamp
protein
thiol
silane
polymer
stamp a
surface
Visualization of Protein Recognition: AFM
BSA
SA monolayer
Stamp
PDMS
PDMS
Stamp
Mica
SA
stamping
SA
Biotin-10nm Au
AFM
Mica
BSA
backfill
Adsorbed protein
Pattern
?
Biotin-BSA-Au
Incubation
Template
imprinting
Imprint
Imprint
Imprint
SA
SA/BSA
co-adsorption
H Shi, B. Ratner, M. Garrison,
Pat Stayton, Sandro Ferari
10 nm Au-biotin bound to adsorbed SA - AFM
150
100
nm
20
0
10
0
50
20
10
20
30
0
50
100
0
150
m
30
40
m
40
Nature, 398, 593-597(1999)
The proteins on mica are disordered -- this is a sub-optimal template!
binding
site
Now
Desired
Imprint
Question: Control at the nanoscale?
binding
site
How will we analyze ordered proteins at interfaces?
• static secondary ion mass spectrometry
SIMS
primary
ions
+
+
+
.. .. ..-secondary
.. ions
+
Macintosh II
+ Static SIMS spectrum of a fibrinogen film
counts/10 2
3
P, R
2.5
V, D
2
1.5
S
F, W
1
0.5
0
50
E, K
H
L
H D
M
70
Y
F
90
R
R M
E
m/z
110
F
W
Y
130
150
Each letter indicates an amino acid
Mantus and Ratner
Y
PC
PCA
Principal Components Analysis
•PC1: direction of the greatest
variance
•PC2: orthogonal axis defining
the next greatest of variance
•Scores: projection of the
samples onto the new PC axes
•Loadings: direction cosines of
the matrix rotation
2
.........
.
.......................
... ..
1
C
P
matrix rotation
X
PCA Distinguishes ToF-SIMS Spectra
0.06
PC 2
(19%)
Hemoglobin
IgG
0.04
Fibronectin
γ-Globulins
0.02
Myoglobin
BSA
0
Papain
Transferrin
-0.02
Collagen
Lactoferrin
Fibrinogen
-0.04
Cytochrome c
Lysozyme
-0.06
-0.08
-0.15
-0.1
-0.05
0
0.05
0.1
PC 1 (53%)
Proteins adsorbed onto mica from 100 µg/mL solutions
Matt Wagner and Dave Castner
Controlling and measuring antibody orientation
Effect of pH on protein charge distribution
Isoelectric point of IgG1, their
fragments, and hCG+
IEP of Fc Isoelectric
Point (IEP)
of antibody
IEP of Fab
Mouse monoclonal anti-hCG
I.E.P.
6.8
Fab
Fc
8.5
6.1
+
2
+
2
dipole
Dipole moment
Fab
Fab
- 2 2
+
+
+
+
Human chorionic gonadotropin (hCG)
Fc
Hua Wang, S. Jiang
Linking SIMS spectra to protein structure
• Information on anti-hCG structure from the protein data bank
can tell us relative composition of amino acids in Fab and Fc:
Amino acid composition ratio Fab/Fc
3.5
TYR
3
2.5
GLY
SER
2
ARG
LEU
1.5
THR
1
0
CYS
VAL
ASP
ILE
0.5
ALA
MET
GLN
PRO
GLU
LYS
T R P
ASN
PHE
HIS
The SIMS Experiment
fab fragment
anti-hCG on
C11NH2
N N N N N N N N N N
H2 H2 H2 H2 H2 H2 H2 H2 H2 H2
anti-hCG on Au
(111)
fc fragment
anti-hCG on
C15COOH
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
Multivariate analysis of SIMS data
scores plot from PCA of Fab and Fc
fragments
PC2(16.32%)
0.03
0.02
0.01
0
-0.01
-0.02
-0.03
-0.04
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
0.04
P
C
1
(
7
9
.
5
7
%
)
fc fragment on Au
fab fragment on Au
Loadings
Loadings plot for PC1 (67.94%) form PCA
0.8
0.6
0.4
0.2
0
-0.2
-0.4
86.097: Leu/Ile
70.0668: Val, Pro,
84.084: Leu/Ile, Lys
Arg
72.08: Val
44.05: Ala,
Lys
60.45: Ser
44.013: Asn 59.049: Arg
120.08: Phe
110.07: His
73.06: Asn
74.06: Thr
72.047: Ala,
71.01: Ser Thr
87.06: Asn
147.04: Tyr
m/z
Hua Wang, S. Jiang
Applying the PCA model to anti-hCG
anti-hCG on
C11NH2
sco res plot from PCA of ant i-hCG
00
.04
PC2(16.32%)
00
.03
00
.02
00
.01
anti-hCG on Au
(111)
0
-00
.01
-00
.02
-00
.03
-00
.04
-00
.05
00
.1
00
.15
00
.2
00
.25
00
.3
00
.35
00
.4
PC1 (79.57%)
ant i-hC G on C 11NH2 S A M s
ant i-hC G on Au sur face
anti-hCG on
C15COOH
ant i-hC G on C 15C OOH SAMs
PCA analysis of the SIMS spectra show differences among anti-hCGs
with different orientations.
dipole
Fab
Fab
N N N N N N N N N N
H2 H2 H2 H2 H2 H2 H2 H2 H2 H2
Fc
IgG molecule
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
H
O
O
C
Using this
alignment,
monoclonal
antibodies to
specific domains
on osteopontin
can be used to
align the OPN.
These can then
be used as
templates for
imprinting.
data from Hua Wang
(in collaboration with Shaoyi Jiang, Chemical Engineering Department)
Adenovirus
Nature knows how to order proteins and deliver protein signals.
Adenoviruses are icosahedral particles. The capsid (protein coat) is built up from
252 capsomers (T=25), of which 240 are hexavalent and 12 (situated at the apices)
are pentavalent. A "penton fibre"projects from each apex.
http://www.uct.ac.za/depts/mmi/stannard/adeno.html
What are the implications of template recognition surfaces?
Immobilized biomolecules on “real” medical
devices have the following limitations:
Hip
prosthesis
Coat with
nanopits for a key
recognition protein
Implant
in bone
The device
concentrates
the body’s protein
•Low stability
•Expensive
•Hard to sterilize
•Prone to contamination
•Complex regulatory position
Heals
into bone
A sugar-coated medical device.
The patient’s own proteins are used for healing.
The Hallmarks of an
Engineered Biomaterial
1. We know which reaction we want to control
2. We know the recognition events to control it
3. We will inhibit non-specific interactions
Nano and Surface skills that will be needed:
non-fouling, immobilization, orientation, mimic, pattern, analysis
WHAT WILL THE FUTURE HOLD?
Biomaterials (2001-2020)
Precison nano-surfaces (2010-2040
Tissue Engineering (2005-2050)
Regenerative medicine (2020+ )
“The art of medicine consists in amusing the patient
while nature cures the disease.”
Voltaire (1694-1778)
J. Donoghue, Brown University
UWEB 2002