© DSM PTG 10/09

The Business of Biomaterials:Innovating at the Bottom of the Food Chain

Bob WardDSM PTG

(Formerly The Polymer Technology Group)Part of DSM Biomedical

Berkeley, CA 94710www.dsmptg.com

© DSM PTG 10/09

DSM

PTG

: Ver

tical

Inte

grat

ion

in

Dev

ice

Dev

elop

men

tLab and Pilot-Scale Synthesis

Component Fab.

Production-Scale Synthesis

Device Assembly

Lab and Pilot-Scale Synthesis

Characterization and QC

© DSM PTG 10/09

(Implantable) Biomaterials as a Business

• Material is often enabling technology for the device or implant• Influencing safety, efficacy, service life• Tailored materials facilitate new designs

• Reduce Healthcare Costs

• Small market size and/or low-volume manufacturing• Typically 1-2% of implantable device sales• High unit costs

• Infrastructure requirements ≡ high volume non-medical markets• High level of technical service required• Must be compliant with Quality Systems (ISO, cGMP)

• QA/QC requirements similar to device manufacturers

• Device manufacturer may under value the material• Very long lead times for commercialization

© DSM PTG 10/09

‘Unconfigured’ Biomaterials: Specialty Chemicals

Thermoplastic Pellets Liquid Resins and Solutions

© DSM PTG 10/09

‘Value-Added’ Biomaterials: e.g. Extruded or Molded and/or Partially Assembled

Tubing for Pacemaker and Neuro-Stimulation Lead Insulation

Sub-Assembly for a Cardiac Assist Device

© DSM PTG 10/09

(Mostly) Implantable Devices and Prostheses

Intraaortic Balloon

Pacemaker & Leads

Sac-type VADVascular Graft

Si-Hy Contact Lens

Hip JointLumbar Spinal Disc

Cervical Spinal Disc

Axial Flow VAD Continuous Glucose Monitor

Diaphragm-type VAD

Dynamic Spinal Fixation Device

© DSM PTG 10/09

Total Biomaterials Market Size (All Uses)

Worldwide Market■ $25.5 billion in 2008■ >$28 billion 2009■ $58.1 billion by 2014: growing at a CAGR of 15.0%

Regional Markets:#1. USA: $22.8 billion by 2014 with a CAGR of 13.6% 2. Europe: $17.7 billion by 2014 with a CAGR of 14.6%

3. Asian market growth: highest CAGR at 18.2%

* Global Biomaterials Market (2009-2014), published by Markets and Markets

© DSM PTG 10/09

2010 U.S. Biomaterials Market

Source: A.Brock, BCC Research, March 2007

Total ≈ $27 billion • Implantable Medical Devices ≈ $10 billion

= Added Value Implantable Biomaterials?

2010

© DSM PTG 10/09

Biomaterials Sales vs. Implant Market Size

USA Medical Implants 2010 Sales:Implants: $100 billion = 100%‘Added-Value Biomaterials’ **: $10 billion = 10%‘Un-configured Biomaterials’ **: $1 billion = 1%

* The Medical Device Market: USA Opportunities and Challenges, Espicom, Jan. 2010 ** Author’s Estimate

USA Medical Implants 2010 Gross Profit:Implants: 75% of $100 billion = $75 billion‘Added-Value Biomaterials’ :** 40% of $10 billion = $4 billion‘Un-configured Biomaterials’ :** 50% of $1 billion = $0.5 billion

© DSM PTG 10/09

Device Manufacturers are Conservative: Why would they use a ‘new’ material in a chronic implant ?

• Satisfy the bulk and surface property requirements of the device or prosthesis

• Obtain a performance advantage over competitive devices

- Improve device safety, efficacy, and/or longevity

• Replace an unreliable or unwilling supplier

• Improve device manufacturing / reduce COG

• Strengthen IP position

• Facilitate regulatory approvalFDA Material Master FileISO and cGMP Quality Systems

© DSM PTG 10/09

Device Manufacturers Want More from Biomaterials

• Artificial Hearts and VADs: Increased flex life and thrombo-resitance for ‘destination devices’

• Pacemakers: More biostable low-modulus insulation materials for thinner, more flexible leads

• Contact Lenses: Low modulus, high O2 and ion permeability and inherently-wettable surface (without surface treatments) → extended wear, generally increased comfort and corneal health at lower cost

• Glucose Sensors: Balanced O2 / glucose permeability, blocking of competitive analytes, without fibrous capsule formation → accurate, linear response andlonger operating life before changing sensor

• Prosthetic Joints: compliance, load distribution, abrasion resistance, compression strength → much longer service life without osteolysis / bone loss in younger patients

• Drug Deliver Devices: Platform technology with easily-variable delivery rate for a variety of drugs

• Degradable Scaffolds: High initial strength, well-known time course of property change during degradation, non-inflammatory (liquid) degradation products.

• Vascular Catheters: Antimicrobial, thrombo-resistant, lubricious, low-cost

© DSM PTG 10/09

Many Possibilities with Polyurethanes:‘The most versatile biomaterial’

• Large number of possible reactants• Hard Segments

• Diisocyanates• Diols » urethane and/or diamines » urea

• Soft Segments• Single Polyol Chemistry • Mixed Polyols

• End groups• Pendant groups

• Many possible structures• Linear• Linear with pendant groups or end groups• Branched or dendtritic• Crosslinked

• Easily synthesized by batch or continuous polymerization• May be designed for biostability or bio-resorption!

Widest range of possible bulk and surface properties:

© DSM PTG 10/09

‘Polyurethanes’ May Also Contain Urea Groups

Polyurethane hard segment formed by reacting diisocyanates with low-MW diols (R1 may be ‘aromatic’ or ‘aliphatic’):

Urea formed by reacting a diisocyanate with an amine:

Urea

AmineIsocyanate

Urethane Urethane

repeatsrepeats

Diisocyanate Diol

© DSM PTG 10/09

Common Diisocyanates for Synthesis of Biomedical Polyurethanes: Reaction w. low MW diol or diamine → polyurethane or polyurea ‘hard segment’

4,4’-diisocyanatodicyclohexylmethane

4,4'-methylene diphenyl diisocyanate

‘Diphenylmethane diisocyanate (MDI)Pure isomer available commerciallyHigh cohesive energy density hard segment with best phase separationMost biostableBest physical-mechanical properties

‘Hydrogenated MDI’ (HMDI)Only isomeric mixtures available Lower cohesive energy / less phase separationLower flex lifeReduced biostability in chronic implantation

© DSM PTG 10/09

Common Polyurethane Soft Segments: Polyalkylene oxides

Tg ≈ -60 ◦CPrimary -OHVery hydrophilicOxidizes in vivo

Tg ≈ -66 ◦C Slower reacting Secondary –OHNo strain-induced crystallization

Tg ≈ -75 ◦C Primary –OHExc. Hydrolytic StabilityReversible strain-induced crystallizationPolytetramethylene oxide (PTMO, PTMEG)

Polyethylene oxide (PEO, PEG)

Polypropylene oxide (PPO)

© DSM PTG 10/09

(Ether-free) Polyhexamethylene Carbonate

CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2 CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2

n

• Produces the strongest & toughest polyurethanes• Compatible with bone and cartilage• Abrasion resistant / low particulate generation• Low permeability to water and gases• Biostable

• Extreme oxidative stability• Excellent hydrolytic stability

• Analogous polyetherurethane may have better flex life

© DSM PTG 10/09

Specialty Polyurethane Soft Segments: Polydimethylsiloxane

YES: → Urea YES: → Urethane

• Presents hydrophobic methyl groups in surface• Silicone rubber analog• Oxidatively and hydrolytically stable• Acts synergistically with organic soft segments to improve

biostability (Ward et al, 1989)• End groups on silicone oligomer is reactive with

isocyanate to form urea or urethane bond: Amine or ‘Carbinol’ > Yes Silanol > No!

• -Si-C- bonds are hydrolytically stable, Si-O-C bond aren’t

NO!: → Siloxane + polyurea

© DSM PTG 10/09

Specialty Polyurethane Soft Segments: Polyisobutylene

HO CH2 CH2 C CH2 OHCH3

CH3 n

• Presents hydrophobic methyl groups in surface• Butyl rubber analog: very low permeability• Tg = -73 °C• Extremely stable to oxidation and hydrolysis• Polyurethanes have lower strength than polyether or

polycarbonate urethanes of otherwise similar composition. (Second soft segment needed?)

• No commercial source for oligomeric diols of reqd. MW?

© DSM PTG 10/09

Biomaterials for Implantable Devices:Satisfying Bulk and Surface Property Requirements

Optimum Bulk ≠ Optimum Surface

● After Device Fabrication:Apply topical treatments or coatings

● Before Device Fabrication:Modify polymers during synthesisUse surface activity and self assembly to achieve the desired surface properties.

Potential Solutions:

© DSM PTG 10/09

Surface Activity and Self Assembly Defined

Self-assembly: The processes in which a disordered system of components forms an organized structure as a result of specific, localized interactions among the components themselves, without external direction.

Surface-activity: The process in which a substance, dispersed as a minor ingredient in the bulk of a liquid or solid, populates the surface in a concentration (much) greater than its concentration in the bulk.

© DSM PTG 10/09

Mechanisms of Interfacial EnergyMinimization in Liquids and Solids

• Surface Area Minimization• Formation of Spherical Drops• Fire Polishing and Solvent Polishing

• Minimization of Unit Interfacial Energy • Migration of Bulk of Components to the Surface: ‘Surface-Activity’• Spontaneous Ordering of Surface Molecules: ‘Self-Assembly’

• Exchange of Surface Molecules Under an Adsorbate• Surface Chemical Reactions• Adsorption / Contamination from the Environment

© DSM PTG 10/09

Surface Activity in a Two-Component System

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

Polymer-Polymer BlendTypical Low-MW Solution

Bulk Concentration

+++

No SurfaceActivity

+++

Bulk Concentration

Surf

ace

Con

cent

ratio

n

Surf

ace

Con

cent

ratio

n

© DSM PTG 10/09

Surface Modification Without Additives: Block Copolymers with (Surface-Active) Self-Assembling Monolayer End Groups (SAME®)

SAME [ ] SAMEPolymer Backbonen

]]n

Surface Properties

= Hard Block

= Soft Segment # 1= Soft Segment # 2

= SAME # 1= SAME # 2

Bulk Properties

© DSM PTG 10/09

What End Groups Can Do In Step Growth Polymers

• Modify Surface Properties• Control Biological Interactions

• Affect protein adsorption• Improve thromboresistance• Provide antimicrobial properties

• Increase Biostability• Affect wettability / contact angle• Reduce coefficient of friction• Increase abrasion resistance

• Improve Consistency• Mono-functional end groups are chain stoppers

• Concentration in reaction mixture determines MW• Improve Thermoplastic Processing

• By limiting molecular weight• Via internal lubrication without the use of low MW additives• By improving mold release and reducing self adhesion

© DSM PTG 10/09

Water Contact Angle and Coefficient of Friction:Bionate® PCU Control vs. Bionate® II PCU with –(CH2)17CH3 End Groups

POLYMER Mean CA [ ° ]

Std. Dev.

Bionate® 55D PCU 78.3 1.6

Bionate® 90A PCU 78.2 .8

Bionate® 80A PCU 76.5 0.5

Bionate® II 55D PCU 97.5 1.5

Bionate® II 90A PCU 98.8 2.3

Bionate® II 80A PCU 97.2 1.3

UHMWPE 104 2.6

Bionate II PCU is Hydrophobic Bionate PCU is Hydrophilic

With

-C18

w/o

-C18

Kinetic COF (ASTM 1894)

Without C18 End Groups: 1.52

With C18 End Groups: 0.41

Surface active, self assembling alkyl groups end groups affect wettability and sliding friction

© DSM PTG 10/09

Improving Biostability with (Fluorocarbon) End Groups:Polyetherurethanes: Intramuscular Rabbit Implants @ 400 % Strain

Polyether-urethane Control: 3-month explant

Polyether-urethane withfluorocarbon end groups:

6-month explant

End Group =-(CF2)nCF3

Ward, et al, JBMR 2006

© DSM PTG 10/09

Antimicrobial Activity: Surface Active, Self Assembling Covalently-Bonded Alkylammonium Halide End Groups Impart Antimicrobial Activity to Thermoplastic Polycarbonate-urethanes

R1:

R2:

PCU: Polycarbonate urethane

© DSM PTG 10/09

Extruded Polycarbonate-urethane Tubing with Non-leaching Antimicrobial End Groups

Bionate Tubing with 0.5 wt% Antimicrobial End Groups

Test Organism: Staphylococcus aureus (ATCC 6538)

Bionate 80A Control Tubing OnInnoculated Media in Culture Dish

Zone of Inhibition Indicates No Leaching:

Antimicrobial Activity Per ASTM E2180-07: Six log reduction of Staph. aureus

© DSM PTG 10/09

Self Assembling End Groups:Self Assembly on Extruded Polyurethane Tubing, e.g. ‘Bionate® II’

Not to scale

© DSM PTG 10/09

Some DSM PTG Thermoplastic Polyurethanes

Bionate® polycarbonate-urethane • CarboSil® silicone-polycarbonate-urethane

• CarboSil® AL aliphatic silicone-polycarbonate-urethane

• Bionate®II polycarbonate-urethane (PCU) with SAME® technology

Elasthane™ polyether-urethane with low MW wax• PurSil® silicone-polyether-urethane

• PurSil® AL aliphatic silicone-polyether-urethane

• Elasthane™II polyether-urethane with SAME™ technology*

Note: All polymer families have FDA Master Files* Developmental material

© DSM PTG 10/09

Continual Improvement of Thermoplastic Polyurethanes for Chronic Implants

Platform Compositions• Aromatic (MDI) Polyether-urethane

• Strong and hydrolytically stable• Aromatic (MDI) Polycarbonate-urethanes

• Very strong and oxidatively stable (when ether free)

DSM PTG EnhancementsVia Composition Changes• Mixed Soft Segments: Silicone-urethane copolymers with enhanced

biostability (Proven in NIH SBIR 1989)• Use of surface activity and self assembly (of end groups) for surface

modification: • Ether-free polycarbonate soft segments

• Improved oxidative stability• Increased toughness

© DSM PTG 10/09

Synthesis of Ether-Free Polycarbonate Diol from Ethylene Carbonate

HO (CH2)6 OHO O

O

HO (CH2)6 O O

O

OH

HO (CH2)6 O O

O

OH

HO (CH2)6 O O

O

+

+

(CH2)6 O O

O

HO (CH2)6 O O

O

Bu2SnOor NaCl

HOOH

+

K

(CH2)6 O O

O

O O

O

+ HO(CH2)6OH (CH2)6 O O

O

(CH2)6 O O

O

HOOH

+

Removal of ethylene glycol in final stage drives the equilibrium from C-2 to form C-6 carbonate

© DSM PTG 10/09

Synthesis of Polycarbonate Diol using Ethylene Carbonate with Ether Formation

Under certain reaction conditions side reactions form etherlinkages susceptable to in vivo oxidative degradation:

O O

O

(CH2)6 OHO O

O

+O O

O

(CH2)6 O

O

O OH

O O

O

(CH2)6 OOH + CO2

Fast

(CH2)6 O O

O

OHO O

O

+(CH2)6 O O

O

OO OH

OFast

-CO2

(CH2)6 O O

O

OOH + CO2

© DSM PTG 10/09

Effect of Ether ‘Contaminant’ on Biostability of Polyhexmethylenecarbonate-urethane

HO-CH2CH2CH2CH2CH2CH2-O-C-O-CH2CH2CH2CH2CH2CH2-O-C-O-CH2CH2OCH2CH2-OH

O O

n m

HO-CH2CH2CH2CH2CH2CH2-O-C-O-CH2CH2CH2CH2CH2CH2-OH

O

x

Resulting polyurethane may be prone to surface oxidation and stress cracking (that generally does not penetrate the bulk beyond ca. 100 µM)

Extremely tough polyurethanes are resistant to surface and bulk oxidation

With Ether:

Ether-free:

Oxidization Here

© DSM PTG 10/09

Improving Accelerated In Vitro Stability with Ether-free Polyol:Polycarbonate urethanes after 407 Hours of Stokes Testing

Polycarbonate-urethane Control (without C18 End

Groups): 407 hours exposure

Ether-free Polycarbonate-urethane (with 0.6 wt % C18

End Groups): 407 hoursexposure

Note: Ether-free PCU

© DSM PTG 10/09

Bionate® II Polycarbonate Urethane (PCU) Properties

0

2000

4000

6000

8000

10000

0 56 111 167 222 278 333

Strain (%)

Stre

ss (P

SI)

80A 90A 55DMolecular Weight [kg/mole] 243

25

8231

518

253 231

Melt Flow Rate [g/10min] @ 224 °C, 2160g load 18 36

Ultimate Tensile Strength (TS) [psi] 8499 8960

Ultimate Elongation (UE) [%] 385 372

6,000 6,500 7,000 7,500 8,000 8,500 9,000 9,500 10,000

80A

90A

55D

Har

dnes

s

Ultimate Tensile Strength (Psi)

Bionate® II PCU 55D Tensile Stress vs. Strain

TS

UE

Bionate PCUBionate II PCU

Avg. 17% Tougher for the three grades

© DSM PTG 10/09

Improved Properties Through Manufacturing Process Changes

Prepolymer SynthesisContinuous Synthesis

© DSM PTG 10/09

Continual Improvement of Thermoplastic Polyurethanes for Chronic Implants

DSM PTG Enhancements

Via Processing Improvements:• Replace batch synthesis with continuous

synthesis by reactive extrusion• On-line feedback for MW control• Reduced particulates• Rapid development of custom polymers

• Gel reduction technologies for higher yields• During polymer synthesis• During extrusion of tubing

© DSM PTG 10/09

Batch Synthesis of Thermoplastic Polyurethanes

Collect PelletizedPolymer

Single-Screw Extruder / Pelletizer

Empty Before Solidification

Complete Rxn. in Oven

Grind Slabs in ‘Wood Chipper’

Feed Granules to Extruder

Start Reaction in Batch Reactor

© DSM PTG 10/09

Continuous Reactor-Extruder Used to Synthesize SAME Polymers, e.g., with C18 End Groups

Cleanroom Collection

Extruder/Reactor

Reactant Feed

© DSM PTG 10/09

Three-Steps to Surface Modified Tubing: Tubing Extruded from Pre-dried ‘SAME Polymer’ Pellets Made by Continuous Synthesis

2. DryPolymer

Pellets

3. Tubing Extrusion and Collection

Tubing Ready for Use

1. Continuous Synthesis of

Pellets

© DSM PTG 10/09

Conclusion: The Importance of Biomaterials in Implanted Devices

• Biomaterials are enabling technology in implantable devices and the key to improved safety, efficacy, longevity and therefore reduced healthcare costs.

• PUs with Self Assembling Monolayer End Groups (SAME®) are a ‘Biomaterials Toolkit’ for rapidly optimizing bulk andsurface properties for specific device applications

• SAME® technology combined with minor (but significant) composition changes and processing improvements created a step improvement in a well-established biomaterial:

• Bionate® II PCU is stronger, more oxidatively stable, more consitant, and more easily processed

• The economics of the biomaterials business, and the conservative nature of device manufacturers and regulators favors the continual improvement of proven platform technologies unless serious short comings are encountered.

© DSM PTG 10/09

Thank You

Additional information at

www.dsmptg.com

DSM PTG2810 7th Street

Berkeley, CA 94710(510)841-8800

© DSM PTG 10/09

Polyurethane Soft Segments: Aliphatic Polycarbonate

CH2CH2CH2CH2CH2CH2 poly(hexamethylenecarbonate)

poly(bisphenol-A carbonate)NOT! :

HO Hbisphenol-A monomer: a hormone-like ‘endocrine disruptor’

• Oxidatively stable when (ether free)• Low permeability

Degradation limited to surface region• Gives very high tensile strength TPUs• Polyol is commercially available