© DSM 6/10

Biomaterials In a New Role: Treatment and Prevention of Infectious Diseases

Bob WardDSM PTG

Part of DSM BiomedicalBerkeley, CA 94710

Keith McCreaEmergence Venture Partners

ExThera Medical LLCBerkeley, CA 94710

© DSM 6/10

DSM Biomedical

Materials that belong to the bodyMaterials that belong to the body

Booth 741www.dsmptg.com

© DSM 6/10

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

• DSM Biomedical supplies materials and license technology to Medical Technology companies for applications within the body, addressing current and future healthcare needs.

• Medical Coatings• Implant Solutions• Drug Delivery

© DSM 6/10

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 6/10

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

• Radiation Crosslinking• High Purity• Controlled Permeability• Phase Mixing In Amphipathic System

© DSM 6/10

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

• PurSil® silicone-polyether-urethane

• PurSil® AL aliphatic silicone-polyether-urethane

• BioSpan® segmented polyether-urethane-urea

All polymer families have FDA Master Files

© DSM 6/10

39 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 6/10

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 6/10

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 6/10

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 6/10

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 6/10

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

© DSM 6/10

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

Not to scale

© DSM 6/10

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 6/10

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® PCU 80A Control Tubing

Zone of Inhibition Indicates No Leaching:

© ExThera Medical LLC 15

Introduction to SeraphTM Affinity Apheresis

© ExThera Medical LLC

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 in order 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

ExThera Medical, formed in 2007, is 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

ExThera Medical is preparing for first clinical trials of an extracorporeal therapy in Q1 2011

* 2007 Spin off from The Polymer Technology Group

HEPARIN: Many Uses and Many More to Come

• The most commonly used blood anticoagulant• Was Discovered by Jay McLean 1926.• Was introduced into the clinic by Erik Jorpes and Clarenc

Crafoord at the Karolinska Institute (during the 1940’s).

THE AT-BINDING SEQUENCE OF HEPARIN

OO

OSO3-

AcNH OOHO

OOSO3

-

OO

OSO3-

CO2-

HO

HOO

OO

OSO3-

-O3SHN O

-O3SO-O3SHNHO HO-O2C

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

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)

Some Clinical Devices that  Currently Use Surface Heparinization

Approved Devices w. 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

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

Heparin Binding Molecules and Pathogens

• Proteins– Cytokines

• TNF-α, IL-6, IL-10– Plasma Proteins

• von Willebrand factor

• ATIII– Growth Factors

• BMP

•Pathogens•Bacteria

•S. aureus•N. meningitidis adhesion through OpcA

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

•Viruses•HIV•Dengue

Mechanism of Binding

• Heparan sulfate proteoglycans, known as syndecans, are found on cell walls

• Syndecans bind and regulate many inflammatory factors through heparan sulfate segments

• Syndecan shedding is part of the inflammatory response, but uncontrolled shedding can compromise the cell surface

• Many pathogens (Hep C, HIV, MRSA, Plasmodium falciparum) and their virulence factors bind to heparan sulfate to subvert the immune response

• Heparin is very similar in structure to heparan sulfate, and is able bind many of the same molecules and pathogens

CYTOKINES, CERTAIN BACTERIA, PARASITES AND VIRUSES BIND TO IMMOBILIZED HEPARIN (BEADS)

THE SURFACE HEPARINIZED POLYMER BEADS

CYTOCYTO

VIRUSVIRUS

ATAT

BACTBACT

PARASITESPARASITES

GFGF

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

© ExThera Medical LLC

Requirements for a Safe and Effective Whole‐Blood Affinity Apheresis Therapy

• Non‐thrombogenic adsorbtion media

• Selective adsorption of ligands

• Adequate capacity with minimum blood hold‐up 

• Good hemodynamics and kinetics for safe blood 

flow through extracorporeal circuits

• Scale‐able for different clinical applications

• Robust, economical device manufacturing process

Potential Applications of Heparin Affinity Therapy

• Sepsis• Cardiogenic Shock• Cardiopulmonary bypass (CPB)

– CABG– ECMO

• Auto‐immune disorders– IBD– Chron’s Disease

• Reduction of LDL

© ExThera Medical LLC

Preclinical Workex vivo and in vitro Studies

Cytokine Removal

Cytokines

• Cytokines are signaling proteins secreted from cells such as leukocytes

• Act as cellular mediators during an immune response

• Tumor necrosis factor (TNF‐α)– Produced by monocytes and macrophages in response to infection

– Present in high‐concentration during inflammatory diseases

Quartz Crystal Microbalance with Dissipation Monitoring (QCM‐D)• Mass change (Δm) on crystal proportional to change in crystal 

resonance frequency (∆f) (Sauerbrey relationship)– Gravimetric method (no labeling)

– Extremely sensitive: ~0.5 ng/cm2

– Real‐time measurements under physiological conditions

– Surface can be modified or coated

Photos taken from http://www.q-sense.comGold Coated QCM Crystal

fn

Cm Δ−=Δ1

overtonensngcmC

−= −− 127,17

Sauerbrey, G Z. Phys. 155 (1959) 206.

QCM Results – Non‐competitive TNF‐α Binding to Exthera Heparinized Surface vs. Control

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

120809_Sau1F3_Fit_Si_37C_TNFa

-100

0

100

200

300

400

500

600

700

800

0 100 200 300 400 500 600

Time (min)

Surf

ace

Con

c (n

g/cm

2)

Exthera Surface Silica Control

< 50 ng/cm2

Removing Cytokines From Blood of Human Septic Patients’

•When passing blood from septic patients through a column packed with surface heparinized beads, it was demonstrated that a significant reduction in concentrations of the pro-inflammatory cytokine TNF-αwas observed, from initially very high levels.

•Passage of blood over non-heparinized beads did not affect the TNF-α levels.

J. Axelsson, M. Ferreira, L. Adolfsson, K. McCrea, R. Ward, and O. Larm, ASAIO 2010, Jan/Feb  

Removing Cytokines from the Blood of Human Septic Patients

• Concentrations of the leukocyte activating cytokine RANTES remained unchanged following passage through the heparinized column, but rose significantly after passage through a column packed with the non-heparinized control beads.

J. Axelsson, M. Ferreira, L. Adolfsson, K. McCrea, R. Ward, and O. Larm, ASAIO 2010, Jan/Feb 

Summary of ex vivo Study

• TNF–α reductions up to 59% obtained with only one pass through heparinized adsorbent media

• IL‐6 reductions up to 24% obtained

• RANTES levels up 466% in control media indicating strong (undesirable) activation of T‐ lymphocyte ex vivo. (Not found with heparinized media.)

Prototype Seraph System Used in Binding Capacity Study

•Seraph cartridge and standard dialysis pump

•Dialysate circuit is not used

In vitro Demonstration of Seraph:  Plasma Dosed with TNF‐α

Experimental Parameters

• Performed at University of Minnesota

• 5 liters of platelet‐poor plasma dosed with high concentration of TNF‐α

• Recirculated at 150 ml/min through a prototype Seraph cartridge for 6 hours at 37 ◦C 

• TNF‐a concentration analyzed with ELISA

Time [min.]

TNF-α

Cle

aran

ce [%

]

J

J

J

J

J

J

J

J

J J J

JJ

JJ

0

10

20

30

40

50

60

70

80

90

0 10 20 30 40 50 60 70 80 90

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 afford clinicians with an effective ‘organ preservation strategy’

Conclusion

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

• New applications in which surface properties are manipulated to create ‘biocompatible’surfaces with selective adsorption will lead to new therapeutic and prophylactic uses, e.g., as alternatives to drugs

© DSM 6/10

Thank You

Additional information available at

Booth 741www.dsmptg.com

DSM PTG / DSM BIOMEDICAL2810 7th Street

Berkeley, CA 94710(510)841-8800