© DSM 4/10

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 4/10

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 4/10

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

© ExThera Medical LLC 3

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 anadsorption bed and returning it to the patient. 

– Safely removes inherently harmful elements (e.g., pathogens), or those that are harmful due to an acute increase in their concentration (e.g., cytokines).

HEPARIN: Many Uses and 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

The Heparinized Surface

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

• Does not adhere thrombocytes

• Does not activate complement, macrophages and granulocytes

• Is bacteriostatic (CVC, IOL)

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 to bind many of the same molecules and pathogens

© ExThera Medical LLC

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

• Non‐thrombogenic adsorbtion media

• Selective adsorption of ligands

• Good hemodynamics and kinetics for safe blood 

flow through extracorporeal circuits

• Adequate capacity with minimum blood hold‐up

• 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

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

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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 a miniature  heparinized adsorbent cartridge

• IL‐6 reductions up to 24% obtained

• RANTES levels increased 466% in controlmedia indicating strong (undesirable) activation of T‐ lymphocyte ex vivo. (Not elevated by 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

80% clearance in 80 minutes:• Performed at University of 

Minnesota

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

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

• TNF‐α 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

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90

0 10 20 30 40 50 60 70 80 90

Potential Use of Seraph Columns to Treat Sepsis

•The Seraph™ column is placed in the extracorporeal circuit to selectively bind and remove molecules from blood (e.g., TNF-α, IL-6) that mediate the inflammatory process

•Lowering the level of circulating cytokines in sepsis ~ the cytokine storm ~ could become 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 4/10

Thank You

www.dsmptg.com

Bob WardDSM PTG / DSM BIOMEDICAL

2810 7th StreetBerkeley, CA 94710

(510)841-8800

Or

Keith McCreaEmergence Venture Partners

Berkeley, CA(510)809-2503