BioForum POSTECH

1
BioForumPOSTECH

• TEST SLIDE

2
BioForum, POSTECH November 17, 2004 Surface
Overcoats on Endovascular Device for Magnetic
Resonance Imaging
Hyuk Yu (yu_at_chem.wisc.edu)
3
Why should we be involved in such an applied
area?
Research universities have changed their
mission Create knowledge, integrate, transmit
apply.
Besides, it feels good to be useful, while
spending public's money its so much fun to
interact with MDs.
Parenthetically, it also earns us more money for
research from licensing incomes.
4
Surface Overcoats on Endovascular Device for
Magnetic Resonance Imaging

• Principal Contributors
• Abukar Wehelie, Intel Corporation, Portland, OR
• Zhihao Yang, Eastman Kodak, Rochester, NY
• Xiqun Jiang, Chemistry, Nanjing University
• Junwei Li, Chemistry, Lehigh University
• Weiguo Cheng, Nalco, Naperville, IL
• Collaborators
• Charles M. Strother, Radiology, Neurosurgery
  Neurology, University of Wisconsin Medical
  School, now Baylor School of Medicine,
  Houston, TX
• Orhan Unal, Radiology Medical Physics,
  University of Wisconsin Medical School
• Richard Frayne, Radiology Clinical
  Neurosciences,
• University of Calgary Medical School, Calgary,
  AB, Canada

5
Medical devices including implants used in the
United States, 2002
6
Magnetic Resonance Imaging
7
How the name came about
Image Formation by Induced Local Interactions
Examples Employing Nuclear Magnetic Resonance
Paul C. Lauterbur, Nature 1973, 242,
190-191. Magnetic Resonance Zeumatography,
Paul C. Lauterbur, Pure Appl. Chem. 1974, 40,
149-57.
8
How does MRI work?
Water is very important for MRI
Nuclei of hydrogen aligns at applied magnetic
field resulting in a net magnetic moment
Precession is crucial to the MRI formation.
Precessional rate is proportional to the
strength of magnetic field, it is in the FM
radio range
9
Fundamentals in MRI

• The contrast of proton MR images depends
  essentially on the following three factors
• 1/T1, the longitudinal relaxation rate, is the
  rate at which nuclei, once placed in a magnetic
  field, exponentially approach thermal
  equilibrium. M(t) M0(1-exp(-t/T1)
• 1/T2, the transverse relaxation rate, is the rate
  at which the MR signal decays. S(t)
  S0(1-exp(-t/T2)
• The density of proton spins in a given volume
• Contrast agents increase the relaxation rate of
  the surrounding nuclei that appear as a bright
  spot of increased intensity in T1-weighted
  images, it is so called positive T1 contrast
  agents. The common contrast agent is DTPA-Gd3
  which has been approved by FDA and in use for
  some time.

10
MRI Contrast agent
11
MRI contrast agentsSafety Issues

• Gd(III) 7 unpaired electrons and large magnetic
  moment, but it is toxic GdXe4f75d16s2,
  Gd(III)Xe4f75d06s0
• Gd(III) chelate, DTPA-Gd(III) relaxivity
  decreases relative to free Gd3 but much safer.
  
• Relaxivity Gd(III) 10.4 mM-1 s-1
  DTPA-Gd(III) 3.8 mM-1 s-1
• LD50 for rat DTPA-Gd(III) 10 mmol/kg
  DTPA around 0.5 mmol/kg
  Gd(III) 0.3-0.5 mmol/kg.
• Clinical dosage DTPA-Gd(III) 0.1- 0.3 mmol/kg

12
MRI and its timeline
MRI an imaging technique used primarily in
medical settings to produce high quality images
of the inside of the human body. Advantages
Safe three dimension imaging.

• MRI Timeline
• 1946 MR phenomenon - Bloch Purcell
• 1952 Nobel Prize - Bloch Purcell
• 1950
• 1960 NMR developed as analytical tool
• 1970
• 1972 Computerized Tomography
• 1973 Back-projection MRI - Lauterbur
• 1975 Fourier Imaging - Ernst
• 1980 MRI demonstrated - Edelstein
• 1986 Gradient Echo Imaging, NMR Microscope
• 1988 Angiography - Dumoulin
• 1989 Echo-Planar Imaging
• 1991 Nobel Prize - Ernst
• Hyperpolarized 129Xe Imaging
• 2003 Nobel prize-Lauterbur Mansfield

13
MR imageable surfaces
Medical devices catheter, guidewire, stent and
other implants.
Advantage It is easy to get information like
the position, shape and how the implants
function without surgery.
Strategy coat the contrast agent typically
DTPA-Gd3 to the surface.
Gd(III) 7 unpaired electrons and with a large
magnetic moment, but it is toxic Electron
configuration, GdXe4f75d16s2,
Gd(III)Xe4f75d06s0
14
Contrast agent
15
The simplest surface coating for MRI
16
Hydrazine Plasma Functionalization of PE Surface
17
DTPAGd(III) Complex Water
18
Attachment of Diethylenetriaminepentaacetic Acid
(DTPA)- Gd(III) Complex to Polyethylene Surface
Gd3 has 7 unpaired 4f electrons, hence T1 of
proton NMR of inner-sphere water is much shorter
than bulk water.
19
Such was imageable in yogurt but in saline
blood!
20
Chronology Review of Coating Designs

• Hydrazine plasma treatment of polyethylene
  surface, covalent attachment of DTPA,
  coordination with Gd(III), imaging in phantom
  (fat-free yogurt), but not in saline and blood.
• NH2-containing carrier polymer tethered on PE
  surface, covalent attachment of DTPA,
  coordination with Gd(III), imaging in phantom
  (fat-free yogurt), but not in saline and blood.
• Assembly encapsulation in hydrogel resulted in
  successful imaging in yogurt, saline and blood.
• Evolution of different designs and successful in
  vivo imaging.
• Understanding of the imaging mechanism.

21
Procedures for preparing MR imageable coatings

• Directly link chemically DTPA to functionalized
  surface,
• without a polymer carrier (less than 1nm)
• with a polymer carrier (around 10nm)
• Hydrogel coating. Contrast agent is trapped
  inside crosslinked hydrogel. (around 50?m)

22
Agarose Gel Encapsulation of Functionalized PE
Rods
(1)
(2)
(3)
23
MRI of Gel Encapsulate of PE Rods(soaked for 1
hour)
1
yogurt
2
3
saline
blood
24
MRI of Gel Encapsulate of PE Rods(soaked for 10
hours)
yogurt
saline
blood
25
Imaging Mechanism

• Interplay between the rotational mobility of
  ligand and the exchange rate of inner sphere
  water Caravan et al., Chem. Rev. 1999, 99,
  2293-2352.
• Difference exists for the imageability between
  spatially confined DTPAGd(III) within a thin
  slab from a surface and that spatially dispersed
  in bulk.

26
Now, the chemical details!
27
Introduction to Different Coating Designs

• Start with SurModics PE surface coated with
  (amine-linked) polymers, chemically link with
  DTPA, coordinate with Gd(III), encapsulate the
  whole package with a soluble gelatin, then
  cross-link with glutaraldehyde, resulting in a
  hydrogel overcoat.
• Start with poly(aminopropyl methacrylamide),
  chemically link with DTPA, coordinate with
  Gd(III), mix with soluble gelatin, coat bare PE
  surface, then cross-link with glutaraldehyde,
  resulting in a hydrogel overcoat.
• Start with gelatin, chemically link with DTPA,
  coordinate with Gd(III), mix with soluble
  gelatin, coat bare PE surface, then cross-link
  with glutaraldehyde, resulting in a hydrogel
  overcoat.

28
Design I
PE rods / SurModics Polymer coating-DTPAGd(III)
/ cross-linked gel
29
MRI enabling coating Design I
Surface composition of PE rods (SurModics) before
and after DTPAGd(III) attachment
30
Coating Fabrication Design I
31
Design II
PE rods / primary polymer with DTPAGd(III) /
cross-linked gelatin gel
32
MRI enabling coating Design II
Attached the ligand (DTPA) to a primary polymer
33
MRI enabling coating Design II
34
MRI enabling coating Design II
35
Design III
PE rods / cross-linked gelatin with DTPAGd(III)
linked
36
MRI enabling coating Design III
Attachment of the ligand (DTPA) to gelatin
37
MRI enabling coating Design III
38
Coating Fabrication Design III
39
Design Progression of MRI Enabling Surface
Coatings
I. Start with PE surface coated with (amino-group
containing) polymers, chemically link with
DTPA, coordinate with Gd(III), coat with a
soluble gelatin and chill set to encapsulate the
whole package, then cross-link with
glutaraldehyde, resulting in a hydrogel
overcoat. II. Start with poly(N-3-aminopropyl
methacrylamide), chemically link with DTPA, mix
with soluble gelatin, coat bare PE surface and
chill set, then cross-link with glutaraldehyde,
and finally coordinate with Gd(III). III. Start
with gelatin, chemically link with DTPA, mix with
soluble gelatin, coat bare PE surface and chill
set, then cross-link with glutaraldehyde, and
finally coordinate with Gd(III).
40
Scan Parameters
1.5 T GE CV Scanner (40mT/m, 150 mT/m/ms)

• 2D SPGR
• TR 18 ms, TE 4.1 ms, Flip angle 30º
• Acquisition Matrix 256 X 256 PE
• Slice thickness 2-3 mm
• FOV 16 cm X 16 cm and RBW 32 kHz
• 2D SE
• TR 300 ms, TE 9.0 ms, Flip angle 30º
• Acquisition Matrix 256 X 256 PE
• Slice thickness 2-3 mm
• FOV 16 cm X 16 cm and RBW 32 kHz

41
Sample Designations, Design I
1 PE-Rod-DTPA-Gd(Gelatin x-linked w/ 0.5
Glutaraldehyde)
2 Two times as thick as 1
3 Three times as thick as 1
4 Four times as thick as 1
5 PE-Rod-DTPA-Gd(Gelatin x-linked w/ 0.1
Glutaraldehyde)
6 Guidewire-DTPA-Gd(Gelatin x-linked w/ 0.1
Glutaraldehyde)
7 PE-Rod-DTPA-Gd(Gelatin x-linked w/ 0.5
Glutaraldehyde)
8 Guidewire-DTPA-Gd(Gelatin x-linked w/ 0.5
Glutaraldehyde)
MR images to follow! When you see one, do you
want to see more?
42
MRI(top view)30? 80?, Design I
T 80 min
T 30 min
Yogurt
Blood
Yogurt
Blood
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
5
1
5
6
2
2
6
7
3
3
7
8
4
4
8
Saline
Blood
Saline
Blood
43
MRI(side view) 30?, Design I
T 30 min
Yogurt
Blood
Yogurt
1
1
1
2
2
2
3
3
3
4
4
4
1
1
5
2
2
6
3
3
7
4
4
8
Blood
Saline
Saline
44
MRI(side view) 80?, Design I
T 80 min
Blood
Yogurt
Yogurt
1
1
1
2
2
2
3
3
3
4
4
4
1
1
5
2
2
6
3
3
7
4
4
8
Blood
Saline
Saline
45
MRI(top view) 30?,Design II
T 30 min
1 PE-Rod
2 Two times as thick as 1
1
Yogurt
3 Guidewire
2
3
1
Saline
2
3
1
2
Blood
3
46
MRI(side view) 30?, Design II
T 30 min
1
Yogurt
2
3
1
Saline
2
3
1
1
2
2
Blood
3
3
47
Comparison MRI, catheter filled with complex vs.
Design III rod, 30 min
III/6 after 30min
5F Cath filled with 4 Gd
48
Comparison MRI, catheter filled with complex vs.
Design III rod, 30 min (2)
III/6 after 30min
5F Cath filled with 4 Gd
49
Design III
III/5 after 30min
6F Cath filled with 4 Gd
50
Design III
III/5 after 30min
6F Cath filled with 4 Gd
51
Design III
III/5 after 30min
52
Design III
53
Technology transfer to the exclusive licensee
54
UW-1
UW-1
UW-1
UW-1
t 30min
55
UW-1
UW-1
UW-1
UW-1
t 30min
56
UW-3s
UW-3s
UW-3s
UW-3s
t 15min
57
UW-3s
UW-3s
UW-3s
UW-3s
t 30min
58
UW-3s
UW-3s
UW-3s
UW-3s
t 30min
59
The end has come!
60
Summary and Conclusions

• 3 different coating designs.
• Successfully imaged in yogurt, saline, blood, and
  canine porcine aorta.
• Visibility / Imageability is dependent on gel
  thickness.
• Optimal gel thickness is dependent on medium
  viscosity.
• lt60 mm in Yogurt
• 60-120 mm Blood
• gt120 mm in Saline
• Visibility / Imageability is independent of
  cross-link density.

61
Uncovered any underpinning basic science issues?
62
Yes, there are two The details of contrast
mechanism Post-plasma ageing of high energy
surfaces
63
Thank you for your patience!
64
(No Transcript)
65
Contrast mechanism
66
Imaging Mechanism

• Interplay between the rotational mobility of
  ligand and the exchange rate of inner sphere
  water Caravan et al., Chem. Rev. 1999, 99,
  2293-2352.
• Difference exists for the imageability between
  spatially confined DTPAGd(III) within a thin
  slab from a surface and that spatially dispersed
  in bulk.

67
MRI contrast agents relaxivity

• Most contrast agents achieve their effect by
  changing the relaxation times of water protons in
  tissues.

Tobs The observed solvent relaxation rate Td
Relaxation rate of the solvent nuclei without
the paramagnetic solute
r1 Proton relaxivity (its unity is mM-1s-1).
Proton relaxivity directly refers to the
efficiency of a paramagnetic substance to
enhance the relaxation rate of water protons.
68
Contrast agent
B0 1.5 T ?2 0.03 x 1020 s-2
To attain maximum relaxivities, rotational
correlation time, proton exchange have to be
optimized. Theoretically attainable value is
over 40mM-1s-1, while the market contrast agents
have relaxivities around 4-5 mM-1 s-1. mainly to
the fast rotation and slow water exchange.
?R can be increased to some extent by increasing
the viscosity of the medium and the molecular
weight of the chelate
69
(No Transcript)
70
Background (1)
71
Background (2)
72
Background (3)
Relaxivity r1 in poly(acrylamide) solution
solution Saline 2 5 10
20 30 50 r1 7.17
7.69 7.66 7.51 7.26 9.35
9.54 (mM-1 s -1) ____________________________ 1
/T1 1/T1,d r1Gd(III)
73
MRI enabling coating Design I
The role of the thickness of gel coating
The MRI performance in of the design I with
different thickness of gel coating (-,
invisible , visible , stronger signal).
The swelling time needed (min) for the MR
signal.
74
MRI enabling coating Design I
The role of the cross-link density of gel coating
The MRI performance in of the design I with
different cross-link density of gel coating (-,
invisible , visible) Gel thickness, 60 mm
75
Viscosity effect on the MRI contrast efficacy of
DTPAGd(III) attached on PE surface
MRI imageablity of PE rods attached with
DTPAGd(III) in viscous solution
76

• If the relaxed protons diffuse too fast, they
  will move far away from the surface during
  imaging time, resulting in no contribution to the
  imageability of rods surface. Such is the case
  when the rod is immersed in saline.
• If the relaxed protons diffuse too slowly,
  DTPAGd(III) on the surface is not well accessed
  by free water, resulting in a slow exchange of
  coordinated water molecules. This would likely be
  the case when the solution is too viscous such as
  with 40-50 PAAm.
• When water molecules near the surface diffuse at
  a suitable rate, the number of the relaxed water
  proton near the surface is maximized during the
  imaging time.
• There is a fine balance between free water
  access to the coordination site of DTPAGd(III)
  and the retention of relaxed water proton in the
  vicinity of the surface. Such may be the case
  when PAAm concentration is from 5-30.

77

• When DTPAGd(III) is dispersed in a PAAm
  solution, the rotational relaxation time of the
  DTPAGd(III) slows down resulting in the
  increase in the relaxivity with viscosity.
• When the DTPAGd(III) is attached on the PE
  surface, it only can enhance the relaxation of
  water proton nearby the surface within a short
  length scale, perhaps about 0.5 nm. Thus, the
  spatial influence of contrast agent is confined
  to the vicinity of the surface.
• The spatial resolution of MRI is around (600mm 5
  600mm 5 900mm). Therefore, it is critical for the
  imageability of the rod surface in MRI to
  increase the average relaxation rate of water
  proton in the imaging region of space (600mm 5
  600mm 5 900mm) near the surface. Hence the
  translational diffusion of relaxed proton close
  to DTPAGd(III) is important.

78
Chemical stability of chelates
79
MRI contrast agentChemical Stability
(dissociation)
(metal-metal exchange)
(ligand-ligand exchange)
M metal ion, L endogenous ligand
K1, K2, K3, ... Kn are stepwise protonation
constants of ligand
80
Binding constants of chelates
81
Post plasma-treatment ageing of hydrocarbon
polymers
82
Spin-off Issue Raised by Plasma
Treatments Post-Plasma Ageing of PS Surface
Surface polarity decay of plasma treated PS
films, stored in relative humidity(RH) 18 after
treatments
83
Post Plasma Treatment Group Migration Picture
84
Surface topography of PS film without plasma
treatment
85
Surface topography of PS film treated by O2
plasma treatment, 100mT, 40W, 1min
86
Surface Roughness of PS Films
Film roughness in the spatial range of 2 ?m does
not change with time, hence it cannot be
responsible for the contact angle changes.
87
Depth profile of treated films vs. storing
timePlasma 100 mT, 40W, 1min Stored in RH 18
88
The relative concentration of different carbon
binding state in treated PS surface vs. ageing
time (take-off angle 15o).Plasma 100 mT, 40W,
1min Stored in RH 18
89
SFG Vibration Spectroscopy of PS Surface
90
SFG Vibration Spectroscopy of Plasma Treated PS
Surface at Different Storing Periods
91
Illustration of the reorientation of polar groups
on PS surface aged in air
92
Summary

• The water contact angle of the plasma modified PS
  surface increases markedly within two days of
  storage in air under 18 RH.
• XPS data suggest that the depth profile of oxygen
  is essentially unaffected by aging, indicating
  that reorganization of chain segments is
  confined in a layer thinner than the probing
  depth of XPS (3 nm).
• Surface roughness can be ruled out as the main
  cause for the change of water contact angle.
• Sum frequency generation(SFG) spectral changes
  with time provide direct support for the
  reactions in plasma treatment involving aromatic
  ring opening, followed by the formation of oxygen
  containing polar groups as side chains.
• When the treated surfaces are stored in air, the
  intensity of CH2 vibration increases with time,
  while that of CH3 vibration decreases, indicating
  that the side chains with polar groups reorient
  toward the polymer interior, while the PS surface
  is covered mostly by polymer backbone. The final
  surfaces however are not those of untreated PS.

93
Confucius in Analect
Studying without thought leads nowhere, whereas
thinking without study results in danger.
94
Library Mall, University of Wisconsin-Madison
95
Memorial Union Terrace by Lake Mendota