Outline • Polyurethane Background • Implantable Polyurethanes: historic challenges • Case Study: Polyurethane in cardiac leads • Next Generation of Implantable Polyurethanes • Future of novel Polyurethanes in long-term implants

1. Next Generation of implantable Polyurethanes
Shrojal Desai, Ph.D.
Manager, Global R&D
Hospira Inc.,
Lake Forest, IL 60044

2. Outline
• Polyurethane Background
• Implantable Polyurethanes: historic challenges
• Case Study: Polyurethane in cardiac leads
• Next Generation of Implantable Polyurethanes
• Future of novel Polyurethanes in long-term implants
• Q&A

3. Polyurethane Chemistry
2 O=C=N-R-N=C=O + HO – R’- OH
+
HO – R’’- OH Chain extender
Polyoldiisocyanate
OCN-R-N-C-O-R’-O
II
O
I
H
-C-N-R-NCO
O
II
H
I
Pre-polymer
-O-R”-O-C-N-
II
O
I
H
-N-C-O-R”-O-
H
I
O
II
Polyurethane
R = Aliphatic
or Aromatic
R’ = polyether
R’’ = hydrocarbon

4. Structure Property relationship
UGUGUGUGU UGU UGUGU
U = Diisocyanate
G = Chain extender
= Hard Segment
= Soft Segment
-O-R”-O-C-N-
II
O
I
H
-N-C-O-R”-O-
H
I
O
II
Polyurethane
Strength
Mechanical stability
crystalline
Flexibility
Elasticity
amorphous

5. Polyurethanes in Medical Devices
-O-R”-O-C-N-
II
O
I
H
-N-C-O-R”-O-
H
I
O
II
Polyurethane
Bio-stable Degradable
Lead insulation
Tubing/Catheters
VADs
Dialysis Membrane
Orthopedics
Prosthetics
Wound Dressing
Device Coating
Adhesives
Others…..
Drug delivery
Tissue Engineering
Wound dressing
Nerve guides
Others….

6. Biodegradable Polyurethanes

7. H H
H
H
H
H
O H5
O
O
H
CH NCOH 2 4
C OO
COCN
CH3
+
PCL
LDI
PCL LDILDI
PCL based amino acid anhydride Polyurethane urea
Amino acid
Amino acid 1 ( G, V, L, I )
Amino acid 2 ( P, A, R, N )
CHNH
H
BocR
O
N
O
NBoc
O
Boc
R R
H
H
OO
R R
HN
O
N
2 2
HCl2
C OO H
US 8,163,865 Biocompatible amino acid anhydride polymers
Shrojal Desai and Buddy Ratner
PCL or PLGA diol
LDI-PCL-LDI
Lysine diisocynate
Mixed Amino acid anhydride
2x
R R
N
O
N NN
N
O
O O
O
OO
N O
O
OO
O
O
4 4 4
n
Pre-polymer
Chain extender

8. Peptide based Polyurethane urea
Polycaprolactone-b-poly(ethylene glycol)-b-polycaprolactone as the soft segment, 1,4-
butanediisocyanate as the hard segment, and the peptide Ala-Ala-Lys as a chain extender.
Guan J and Wagner W.,
Biomacromol. 6, 2833 (2005)
PCLPEG diol
Peptide diamine
Butane diisocyanate
PEG -co-PCL diol

9. Biostable Polyurethanes

10. Polyurethanes in Medical Devices
-O-R”-O-C-N-
II
O
I
H
-N-C-O-R”-O-
H
I
O
II
Polyurethane
Stable Degradable
Lead insulation
Tubing/Catheters
VADs
Dialysis Membrane
Orthopedics
Prosthetics
Wound Dressing
Device Coating
Adhesives
Others…..
Drug delivery
Tissue Engineering
Wound dressing
Nerve guides
Others….

11. Co- radial
Co-axial
Lead body
insulation
Cardiac pacing Leads
Proximal end
Distal end

12. SILICONE RUBBER
Soft Segment
Cross-linked
Hard Domain
Silica filler
Common Pacing lead insulation materials
POLYURETHANE
H-bonded
Hard Segment
Soft Segment
Silicone and Polyurethane have been used for 30+ years with great success!

13. Limitation: A small number of lead insulation fails due to mechanical or chemical degradation
Lead -to- PG can
Lead -to-Lead
Lead/suture sleeve
Lead body-to-coil
Degradation, MIO
Stress cracking
Stress cracking
Cautery damage
Benefits: Processing, Strength, Abrasion
resistant, Thinner insulation
Issues: Chemical Stability, Stiffness
SILICONE
Issues: Processing, Strength, Abrasion,
Thicker insulation
Benefits: Chemical Stability, Flexible
Lead insulation current state
POLYURETHANE

14. ESC – MIO background
Environmental Stress Cracking
• Requires residual/ induced stress in PU
• Foreign body response to implants
• Predominantly a surface phenomenon
• Results in superficial surface cracking
• Minimum or No change in bulk Tensile/
Elongation properties
• No visible changes in FTIR spectra
Metal Ion Oxidation
• Requires corrosion products/ transition
metals with oxidation potential > 0.7 V
• Accelerates PU degradation in presence of
stress and stress cracks
• Deep cracks in the PU
• Serve loss of mechanical properties
potentially leading to catastrophic failure
• FTIR shows loss of Ether soft segments
20 um35 um
Coury et al., Degradation of Materials in Biological Environment. Biomaterials Science, Academic Press

15. Degradation in Biological Environment
Coury et al., Degradation of Materials in Biological Environment. Biomaterials Science, Academic Press
http://courses.washington.edu/conj/bloodcells/oxygenradicals.htm
*
Cross-link
Chain scission
* Site for Homolysis

16. Overcoming the limitations of PU and PMDS

17. Common Pacing lead insulation materials
Poly (SILOXANE-Co-URETHANE)
20 % Polyether (PHMO)
80 % Polydimethylsiloxane
Gunatilake et al.,
at CSIRO, Australia
SILICONE RUBBER
Soft Segment
Cross-linked
Hard Domain
Silica filler
POLYURETHANE
H-bonded
Hard Segment
Soft Segment

18. * Results are not independently confirmed
Source: http://www.sjmprofessional.com/
5 Optim with Fast-Pass™ coating
Optim™ insulation…7 years into making !
Exclusively licensed to St. Jude
AbrasionperformanceFlexibility
tweaking
Originally developed by AorTech as Elast-Eon ™
< 6Fr< 7Fr
’s approach:
Overcoming the limitations of PU and PMDS

20. Exclusively licensed to Medtronic
SI-PI coating
Co-radial
Polyurethane 55D
Benefits of LaRC SI insulation:
• SI-PI being a micro-thin coating helps
achieve small lead body diameters
• Good hydrolytic stability
• Good electrical insulation properties
• Good abrasion resistance
Attain Ability® (4 Fr LV Lead)
LaRC SI
Developed by
Based on Medtronic’s Patents
on the use of LaRC SI for Leads
…… 10 years into making !
tweaking
Overcoming the limitations of PU and PMDS
Medtronic’s approach:

21. OH
HO
OCN NCO
Toluene
Sn(Oct)2
HO
OH
O
O
N
H
O
*
H
N O
O
O N
H
O H
N *
O
Polyisobutylene Polyurethane (PIB-PU)
Durometer - 55A to 55D
Overcoming the limitations of PU and PMDS
’s approach:

22. PIB-PU based block copolymers
PIB-MDI BDO-MDI PTMO-MDI
OH
HO
H
O
OH+
HO-Allyl-PIB-Allyl-OH
Mn = 2200
HO-PTMO-OH
Mn = 1000
OCN NCO
Toluene
Sn(Oct)2
100 oC
HO
OH
PIB O N
H
O
*
O H
N O
O
O
N
H
O H
N O PTMO
O
O
H
N
O
N
H
*
O
1.
2.
90 : 10
to
10 : 90
PIB Diol
US Pat. Applications: US12492440, US2492483, US12563733, US12784559, and US12874887

23. Accelerated Biostability Test
Soak in strong oxidative solutions of 20% H2O2
and 0.1 M CoCl• 6H2O in water at 50°C.
Measurement taken at 0, 1, 2, 4, 6, & 12 weeks:
– Weight loss (physical)
– ATR-FTIR (chemical analysis)
– NMR (chemical analysis)
– SEM imaging (optical)
– Stress-Strain (mechanical)
– GPC (structural)
Composition
PIB/PTMO
Shore A Hardness
60A 80A 100A
70/30 X
80/20 X X X
90/10 X X X
Before measurement the samples are washed 7 times in 1% Triton X-100 solution,
5 times in ethanol, 5 times in distilled water, then vacuum dried until constant weight
Simulated MIO/ESC Testing

24. Weight loss Data
PIB based polyurethane were found to be more biostable than Pellethane™

25. SEM Images
0weeks6weeks
60A 82 80A 82 100A 82P 55D P 80A
PIB based PUControls
The PIB segment acts as a barrier surface and delays the degradation of PTMO segment in these
PIB-PTMO TPUs
12weeks
Complete
Disintegration
Complete
Disintegration
60% 65% 16% 12 %13%PTMO

26. FTIR Spectra

27. Pellethane®Polyisobutylene Polyurethane (PIB-PU)
Better Bonds and Joints
•Thermal fusion
•No more PU to Silicone bonds
Simplified Lead Body Designs
• Elimination of redundant insulation
• Tunable Stiffness along the lead body
Biostability at Low Durometer
• Eliminate Environmental Stress
• Immune to (MIO) degradation
Better Manufacturability
•Eliminate Solvent swelling and Medical Adhesives
•Stable low Durometer enables advanced molding/extrusion
Better Implant Experience
• Maneuverability (optimum stiffness/flexibility)
• Soft, Atraumatic Tip (perforation control)
Enable Smaller Lead Diameters
• Tapered shaft, bump, co-extrusions
• Abrasion Resistance/ Thinner Walls
Durometer - 55A to 55D
Overcoming the limitations of PU and PMDS
’s approach:
100 oC
HO
OH
PIB O N
H
O
*
O H
N O
O
O
N
H
O H
N O PTMO
O
O
H
N
O
N
H
*
O
2.

28. 31
Summary
• PIB based polyurethanes with Durometer ranging from 50 A – 55D
were successfully synthesized and extruded.
• PTMO in additive proportions acts as a compatibilizer and is critical to
achieving good mechanical properties of the PIB-based PUs.
• Saturated PIB-PU is colorless and is more preferable over unsaturated
PIB-PU.
• PIB-PUs showed least weight loss compared to the Pellethane™ and
ElastEon™ controls in our in vitro bio-stability tests carried out to
simulate MIO/ESC .
• “Silicone-like” thermoplastic PIB-based PU demonstrated excellent
physical, mechanical and chemical stability .

29. Prof. Kennedy’s work on PIB-PU
• In early 1970s Prof. Joe Kennedy’s and his coworkers pioneered the
development of telechelic PIBs with allyl/vinlyl groups.
HO OH

30. Prof. Kennedy’s work on PIB-PU

31. The search for a truly biostable long-term implantable
polyurethane may not be over yet, however for the first
time in three decades we are so close to realizing the
dream of a biostable polyurethane that is developed to
meet the requirements for long-term implant.

32. ACKNOWLEDGEMENTS
Boston Scientific Corp., MN
Dr. Mark Boden
Dr. Mohan Krishnan
Dan Cooke
Mike Smith
Kasyap Seethamraju
UMass, Lowell, MA
Prof. Rudi Faust
Dr. Umaprasanna Ojha
Dr. Pallavi Kulkarni
University of Washington, WA
Prof. Buddy Ratner
Dr. Esmaeel Naeemi
Dr. Felix Simonovsky
Coleen Irvine

33. THANK YOU ALL FOR YOUR TIME