© DSM 9/2010

Therapeutic Applications of Surface Modified Biomaterials:Treatment and Prevention of Infectious Diseases

Bob WardDSM PTG

(DSM Biomedical)Berkeley, CA

Keith McCreaEmergence Venture Partners

ExThera Medical LLCBerkeley, CA

© DSM 9/2010

DSM Biomedical

Materials that belong to the bodyMaterials that belong to the body

© DSM 9/2010

A new business area for DSM in a high potential market

Broad portfolio enables crossover innovation

• Started in 2004 building on DSM’s skills, expertise and facilities in Life Sciences and Materials Sciences

• We supply materials and license technology for medical applications addressing current and future healthcare needs.

• Medical Coatings• Implant Solutions• Drug Delivery

© DSM 9/2010

Building on DSM Competences

• Technology • DSM Desotech (UV-curing)• DSM Research (coatings) • DSM Resolve (analysis)• DSM Materials Science (performance)• DSM Aces (physical analysis)• DSM NeoResins (metal primer)

• Antimicrobial Knowledge• Life Sciences R&D Delft, • Life Sciences R&D Geleen

• c-GMP production• DSM Rescom (Regensburg)• DSM Pharma Products (Greenville)

DSM Metal Primer

Synergy between Life Sciences & Materials Sciences

© DSM 9/2010

Coatings and

Implants

Polymer enabled drug

delivery

Coatings and

Implants

Medical Coatings and

Polymers

Resorbable Polymers andDrug Delivery

Therapeutic Materials and Regenerative

Medicine

BIOSTABILITY BIOCOMPATIBILITY BIO-INTERACTIVE

Our Strategic Pathway

BionateBionate®® PCUPCUCarboSilCarboSil®® TSPCUTSPCU

ComfortCoatComfortCoat®® coatingscoatingsDyneema PurityDyneema Purity®® fiberfiber

Various other products and Various other products and research programsresearch programs

TrancertaTrancerta™™ Drug Delivery Drug Delivery

Preferred partner for Pharma Preferred partner for Pharma and Medical Device Industryand Medical Device Industry

Explorative efforts in closeExplorative efforts in closecooperation with public and cooperation with public and

private partnersprivate partners

© DSM 9/2010

40 Years of Cardiovascular Applications:Polyurethanes in Chronic Implants

AVCO IAB 1971

TCS HeartMate® LVAD

Jarvik III TAH

Thoratec PVAD and IVAD

Jarvik 2000

Abiomed BVSAbiocor TAH

Thoratec HeartMate II

Vectra™Vascular Graft

Sunshine Heart C-Pulse™ 2009

Pacemakers (Various)

© DSM 9/2010

DSM PTG: Silicone-Hydrogel ‘Monomer Mixes’ & Precursors, Membranes, Coatings, Drug Delivery, etc.

• Visible Light or UV-Initiated Crosslinking• High Purity• Controlled Permeability• Phase Mixing In Amphipathic Systems

© DSM 9/2010

DSM PTG Polyurethanes in Orthopedics

AxioMed Freedom®

Lumbar DiscZimmer Dynesys®

Dynamic Spinal Stabilization System

• Over 14 years global experience

• Over 40 thousand procedures

• CE Mark received

• IDE pivotal study initiated

© DSM 9/2010

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

SAME [ ] SAMEPolymer Backbonen

]]n

Surface Properties

= Hard Block

= Soft Segment # 1= Soft Segment # 2

= SAME # 1= SAME # 2

Bulk Properties

© DSM 9/2010

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 9/2010

What End Groups Can Do In Step Growth Polymers

• Modify Surface Properties• Control Biological Interactions

• Affect adsorption onto surfaces• Affect cellular interactions• 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 9/2010

Sum Frequency Generation (SFG) Vibrational Spectroscopy:Analysis of the outer-most molecular monolayer ‘wet or dry’

© DSM 9/2010

Some DSM PTG Biomedical Polyurethanes

• Bionate® polycarbonate-urethane

• Bionate® II polycarbonate-urethane with SAME

• CarboSil® silicone-polycarbonate-urethane• CarboSil® AL aliphatic silicone-polycarbonate-urethane

• Elasthane™ polyether-urethane with low-MW wax additive

• Elasthane™ II polyether-urethane with SAME™ processing aid

• PurSil® silicone-polyether-urethane• PurSil® AL aliphatic silicone-polyether-urethane

• BioSpan® segmented polyether-urethane-urea

All polymer families have FDA Master Files

© DSM 9/2010

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

Not to scale

© DSM 9/2010

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

Polyether-urethane Control: 3-month explant

Polyether-urethane with fluorocarbon end groups:

6-month explant

Ward, et al, JBMR 2006

© DSM 9/2010

Extruded Polycarbonate-urethane Tubing with Non-leaching Antimicrobial SAME

Bionate® Tubing with 0.5 wt% Antimicrobial End Groups

Test Organism: Staphylococcus aureus (ATCC 6538)

Bionate® PCU 80A Control Tubing

Zone of Inhibition Indicates No Leaching:

© ExThera Medical LLC 9-2010 16

Introduction to SeraphTM Affinity Apheresis

Presented by ExThera Medical LLC

© ExThera Medical LLC 9-2010

Apheresis in Extracorporeal Therapy

The process of removing specific components from whole blood by passing it through an adsorption bed and returning the treated blood to the patient to remove elements that are inherently harmful (e.g., pathogens), or harmful due to acute increase in their concentration (e.g., cytokines).

© ExThera Medical LLC 9-2010

Requirements for a Safe and Effective Affinity Apheresis Therapy

• Non‐thrombogenic and non‐leaching adsorbtion media

• Selective adsorption of ligands

• Adequate capacity with minimum hold‐up volume

• Good hemodynamics and kinetics for safe flow 

through extracorporeal circuits

• Scale‐able for different clinical applications

• Robust, economical device manufacturing process

19

ExThera Medical, LLC

ExThera Medical, formed in 2007 as a joint venture between Emergence Venture Partners, Berkeley, CA and ExThera AB, a technology transfer company at the Karolinska Institute, Stockholm, Sweden

ExThera AB is a technology-focused R&D firm based on the life work of Professor Olle Larm, a pioneer in the study of heparin and its many attributes

The Company is preparing for first in man clinical trials for an extracorporeal therapy in Q1 2011

19

20

Seraph (Selective Removal by ApApheresis)

Exthera Medical has developed a novel affinity apheresis blood filter to down‐regulate the inflammatory response

The technology is based on covalently‐bonded, ‘end‐point attached’ heparin

Surface‐bound/immobilized heparin provides blood compatibility and the ability to bind and remove inflammatory molecules, pathogens, and virulence factors from the blood

20

21

SURFACE HEPARINIZED MEDICAL DEVICES

• Clinicians wanted a stable coating of heparin on medical devices e.g., dialyzers and oxygenators, while reducing the need for systemic heparinization that causes bleeding problems in long term use

• In 1982 Professor Larm covalently linked heparin to polymeric surfaces while retaining anticoagulant activity, • End-Point Attachment:

• The CARMEDA* Process

*A registered trademark of Carmeda AB, STOCKHOLM, SWEDEN

21

22

BIOCOMPATIBILITY OF THE HEPARIN SURFACE 

• Does not activate the coagulation system (non-thrombogenic)

• Does not adhere thrombocytes• Does not activate complement,

macrophages and granulocytes• Is bacteriostatic (CVC, IOL)

22

23

Some Clinical Devices that  Currently Use Surface HeparinizationApproved Medical Devices Using End-point Attached

Heparin:Medtronic Maxima Oxygenator-Cardiopulmonary Bypass Circuit: CE Mark and FDA ApprovalThe Diametrics Paratrend Intravascular Blood Gas Sensor Catheter: CE Mark and FDA approvedThe Pharmacia CeeOn Intraocular Lens: CE Mark and FDA ApprovalThe Berlin Heart ventricular assist devices EXCOR and INCOR: CE MarkThe Cordis Bx Velocity Coronary Stent Hepacoat: CE Mark and FDA Approval

23

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Other Properties of Heparin

• Anti‐inflammatory– Binds chemokines, growth factors, adhesion molecules, cytotoxic 

peptides, and tissue destructive enzymes

– Journal of Cardiothoracic and Vascular Anesthesia, 18, 1 February 2004: pp 93‐100

• Anti‐microbial– Heparan sulfate and heparin can bind pathogens (viruses, bacteria, 

parasites) and bacterial virulence factors.

– Mol. Cells OS, 26, November 2008: pp 415‐426

24

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Heparin Binding Molecules and Pathogens

• Proteins– Cytokines

• TNF-α, IL-6, IL-10– Plasma Proteins

• von Willebrand factor

• ATIII– Growth Factors

• BMP

25

•Pathogens•Bacteria

•S. aureus•N. meningitidis adhesion through OpcA

•Virulence Factors•S. aureus – α and βtoxins•S. pneumoniae - ZmpC

•Viruses•HIV•Dengue

26

QCM Results – Non‐competitive TNF‐αBinding to Exthera Heparinized Surface

26

100331_12Hep_34PS_TNFa_37C_x1

-600-400-200

0200400600800

1000120014001600

0 200 400 600 800 1000 1200

Time (min)

Surf

ace

Mas

s (n

g/cm

2)

1234 ng/cm2

27

QCM Study Conclusions

• The control samples demonstrates negligible TNF adsorption

• Heparinized polystyrene demonstrated a maximum adsorption of 1234 ng/cm2

27

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Prototype Seraph Cartridge for Binding Capacity Study

•Seraph cartridge and standard dialysis pump

•Dialysate circuit is not used

29

Potential Use of Seraph Columns to Treat Sepsis

The Seraph™ filter is placed in the extracorporeal circuit to selectively bind molecules (e.g., TNF-α) that mediate the inflammatory process. This lowering of the circulating level of cytokines in sepsis ~ the cytokine storm ~ could reduce the likelihood of organ failure and thereby provide clinicians an effective ‘organ preservation strategy’

29

Conclusion

• Biomaterials have traditionally been used to augment, repair or replace damaged body parts.

• New applications in which surface properties are manipulated to provide selective adsorption will lead to new therapeutic and prophylactic uses, e.g., as alternatives to drugs

Thank You

Additional information available atwww.dsmptg.com

Keith McCreaEmergence Venture Partners

Berkeley, CA(510)809‐2503