r&d/manufacturing of biomaterials and medical … · r&d/manufacturing of biomaterials and...
TRANSCRIPT
R&D/Manufacturing of Biomaterials and Medical Devices (with Jim’s Help)
Avco Medical Products (1971 - 1978)Thoratec / Mercor (1978 - 1988)
Polymer Technology Group (1989 - 2010)ExThera Medical Corporation (2010 - Now)
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Processing/Conversion Clean Room Device Assembly
Lab & Pilot Batch Synthesis <1-100 L Production Synthesis 10-1000 gal.
Characterization and QC
Biomedical Polymers: The Ideal
A Practical Biosurface Polymer Chemistry
“…organic functional groups designed and introduced onto
man-made surfaces to control the biological
interactions…yielding tailor-made surfaces.” *
How can this be done?
1. With coatings & topical treatments
2. Through understanding and application
of Surface Activity and Self Assembly of
soft blocks and end groups →
‘SMAs, SMEs and SAMEs’
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(Polyurethane) Block Copolymers with ‘SAME’:
‘A Biomaterials Toolkit’
SAME [ ] SAME*Polymer Backbonen
]]
n
Surface Properties
= Hard Block
= Soft Segment # 1= Soft Segment # 2
= SAME # 1= SAME # 2
Bulk Properties
*Note: ~1018 end groups/gram of linear polymer @ 100K Da.
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End Groups Can Modify Important Surface Properties
• Biostability
• Lubricity / Low Sliding Friction
• Thrombo-resistance
• Anchoring Bioactive Molecules
• Protein Adsorption
• Abrasion Resistance (Roller Pump)
• Antimicrobial Activity
• Permeability of Dense Membranes
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r
Liquid Reactants In
Continuous Reactor for Bulk Synthesis of Thermoplastic
(Co)Polymer Pellets: For Injection Molding and Extrusion
Pelletized
Product
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Biomedical Polymers Developed and Commercialized
• Bionate® polycarbonate-urethane by continuous synthesis
• Bionate®II polycarbonate-urethane with SAME surface modification
• CarboSil® silicone-polycarbonate-urethane copolymer
• Elasthane™ polyether-urethane (Pellethane-2363 replacement)
• PurSil® silicone-polyether-urethane copolymer
• PurSil® AL aliphatic silicone-polyether-urethane copolymer
• BioSpan®/ Cardioflex™ segmented polyether-urethane-urea
• Thoralon™ surface-modified segmented polyether-urethane
• Angioflex™ / Avcothane™-610 high-purity polyetherurthane
• Avcothane™-51 / Cardiothane™ silicone-polyurethane hybrid (scale up)
All PTG Polymers have FDA Master Files↑
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Some Blood- and Tissue-Contacting DevicesThat Use our Biomedical Polymers
• Intraaortic Balloon
– Avco/Kontron/Arrow
• Sac and Diaphragm VADs
– Thoratec, ThermoCardio, Sunshine Heart, Hershey Medical Center, others
• Vascular Access Graft
– Bard (Thoratec Vectra® )
• Pacemakers and Leads
– Medtronic
• Neuro-stimulators and Leads
– ANS/St. Jude
• C-V Catheter
– Vygon
• Continuous Glucose Sensors
– Dexcom, Medtronic
• $ilicone-Hydrogel Contact Lense$
– Vistakon: Acuvue Advance, Oasys, and TruEye
• Prosthetic Cervical Disc
– Medtronic Bryan Disc
• Prosthetic Lumbar Disc
– Axiomed Freedom Disc
• Dynamic Spinal Fixation Implant
– Zimmer Dynesys®
• Anti-Viral Drug Delivery
– Conrad TFV LNG Intravaginal Ring
Monolayers Matter! : In Vivo Platelet Thrombus on Catheters is Reduced Three Orders of Magnitude by Amphiphilic Terpolymer
‘Surface Modifying Additive’ (SMA): ‘Thoralon™’
γ
Camera
Goat
Control PU
Surface Modified PU
Experiment in progressRadiolabled platelet
uptake vs timeVentricular assist
device (VAD) explants
w/o SMA
w. SMA
≈1000-fold reduction in adherent platelets
on modified PU catheter
Thoratec PVAD & IVAD
Clots
43 Years of Biomaterials for Blood-Contacting Cardiovascular Devices
AVCO IAB 1971:
First Cardiac
Assist Device
Sunshine Heart
C-Pulse* 2010
Thoratec Vectra™ Vascular Access Graft
TCS HeartMate® LVAD
Jarvik III
TAH
Thoratec PVAD
Kantrowitz
CardioVad™
Abiomed BVSAbiocor TAH
Thoratec IVAD * No blood contact
Therapeutic Applications of Biomedical Polymers:
Curing Bloodstream Infections with Polymeric Adsorbents
Bob Ward and Keith McCrea
ExThera Medical Corporation
Berkeley, CA 94710
www.extheramedical.com
Bloodstream Infections Are Becoming More Deadly
• (Over) use of anti-infective drugs promotes resistance
• Slow pathogen ID delays treatment:
– Metastatic infections and septic shock may result
– Mortality increases 7% / hour of delayed treatment ! *
• Rapid treatment prevents progression and reduces ICU costs
• A safe, broad-spectrum, disposable device may be the answer!
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*Kumar A, Roberts D, Wood KE et al. Crit Care Med. 2006;34:1589-96
Methicillin Resistant Staphlococcus aureus (MRSA):Binds to Heparin/Heparan Sulfate
MRSA Bacteremia Incidence:– Leading cause of bacteremia in hospital
patients: 18.8%
– An emerging global pandemic
Metastatic Complications:– Infective endocarditis
– Septic arthritis and osteomyelitis
– Organ involvement (lung, liver, spleen, brain)
Mortality: Over 36% from MRSA!
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Warnings from Trusted Sources
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“Bacteria will inevitably find ways of resisting the antibiotics we develop, which is why aggressive action is needed now to keep new resistance from developing and to prevent the resistance that already exists from spreading.” (U.S. CDC)
“The problem of
antimicrobial
resistance calls for
international
cooperation, as well
as concerted efforts
at the national level.”
(ECDC)
“The WHO’s first global report on antimicrobial resistance, reveals that it is no longer a prediction for the future. Antibiotic resistance—when bacteria change and antibiotics fail—is happening right now, across the world”
Antibiotic crisis
needs united global
response 23 May 2014
“Growing resistance
among pathogens to
antibiotics and other drugs
demands a coordinated
global response on the
same scale as efforts to
address climate change,
say experts including Dr
Jeremy Farrar, Director of
the Wellcome Trust.
Without an international
commitment to tackle the
issue, the world faces a
future in which simple
infections that have been
treatable for decades
become deadly diseases,
they warn.”
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Blood Pump
One Device to Remove Pathogens, Toxins and
Pro-inflammatory Cytokines from Whole Blood
Seraph® Microbind® Affinity Blood Filter:A broad-spectrum adsorption-hemoperfusion device
Dual-lumen Central
Venous Catheter
Design Control Inputs for a Safe and Effective Sorbent Hemoperfusion Device
1. A disposable broad-spectrum biomimetic, whole-blood sorption hemoperfusion device
a. Binds bacteria, viruses, parasites, toxins and pro-inflammatory cytokines
Works on drug-susceptible and drug-resistant pathogens
2. Rapid kineticsa. Convective transport of adsorbates to binding sites
• No rate-limiting diffusion into mesopores or through membranes
→No size exclusion of (cellular) adsorbates
3. Very high binding capacity per unit weight of adsorbent
4. Highly anti-thrombogenic blood-contacting surface
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Design Control Inputs for a Safe and Effective Sorbent Hemoperfusion Device
5. Pathogens do not die and release toxins when adsorbed
6. Treats whole blood without fractionation
7. Simple design is easily scaled up for manufacturing
8. Disposable component has multi-year shelf lifea. Stored dry at room temperature
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Anand Kumar MD, University of Manitoba
From Late InterventionAntimicrobial Drug Therapy
To Early Antimicrobial Device Therapy with Seraph®
A Paradigm Shift:
RITYEVE S
RITYEVE S
Treating BSI to Prevent Sepsis & Septic Shock
Microbial load
Inflammatoryresponse
Toxic burden
TIMEt(a) t(b)
TIME
Toxic burden
Microbial load
Antimicrobial
therapy
Cellular dysfunction/tissue injury
earlier antimicrobial
therapy (Seraph ®
Shock
Threshold
Cellular dysfunction/tissue injury
Inflammatory response
Shock
Threshold
t(a) t(b)
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Biomimetic Binding in Seraph Media:Heparin ≈ Heparan Sulfate (glycosaminoglycans)
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heparan
sulfate
Cell Surface
ATIII
peptide backbone pathogen
ATIII
ATIII
ATIIIATIII
Surface of
Seraph Media
heparin
toxin
Some of the Pathogens that Bind to Heparin/Heparan Sulfate
23 © ExThera Medical 2/13
Bacteria
S. aureus Endocarditis, Meningitis, Sepsis
MRSA Flesh Eating Bacteria,Endocarditis, Meningitis, Sepsis
Borreliaburgdorferi
Lyme Disease
Strep. pyogenes
Scarlet Fever, Strep.Throat, Toxic Shock Syndrome
Strep. pneumoniae
Pneumonia, Sepsis, Meningitis, Endocarditis
Viruses
CMV Organ Failure
Dengue Hemorrhagic Fever,Dengue Shock Syndrome
Hepatitis C Liver Failure, Cancer
HIV Aids
West Nile Encephalitis, Meningitis
Parasites and Other
Babesia Malaria of the Midwest
Plasmodium spp. Malaria
T. cruzi Chagas
Prions Mad Cow Disease, vCJD
Removal of Pro-inflammatory Cytokine from Porcine Plasma by Seraph: TNF-α
• 50% Reduction @30 min.
• 80% Reduction @80 min.
• 5 liters of plasma dosed with TNF-α at 83 µg/L
• Circulated at 150 mL/min through a Seraph cartridge back to a large blood bag
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Constant 80%
reduction of inlet
concentration
Time [min.]
Drug-Resistant BacteriaGram Positive
BacteriaGram Negative
BacteriaViruses, Fungi, and
Toxins
MRSA S. aureus E. coli HSV-1, HSV-2
CRE - E. coli and K. pneumoniae
S. pneumoniae K. pneumoniae C. albicans
ESBL - K. pneumoniae E. faecalisAcinetobacter.
baumannii Endotoxin*
VRE - E. faecalis E. faecium P. aeruginosa*S. aureus
a-hemolysin
Current List of Successful In Vitro Results
Considered “URGENT THREAT” by CDC
Seraph® Microbind ®
Affinity Blood Filter
Drug resistant bacteria removed as easily as drug susceptible Lowering bacteria and toxin loads should allow antibiotic
treatments to be more effective No need to identify which bacteria is causing the infection
• Allows early treatment and better outcomes
Considered “SERIOUS THREAT” by CDC
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Expanding Seraph’s Binding Capacity to Include Endotoxin
• Endotoxemia is common during sepsis regardless of infecting organism
• Initial gram negative organism, or leaky gut
• High-grade endotoxemia increases mortality
• Endotoxins bind to (cationic) surfaces that are thrombogenic….not to heparin
• Can heparinized media in close proximity to thrombogenic surfaces prevent thrombosis ??
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(Thrombogenic) Supplemental Adsorbent Gives Seraph Ability to Safely Remove Endotoxin
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Human blood with LPS* (10 ng/mL)
circulated through Seraph columns
at 150 mL/min for 2 hr.
LPS Reduction (n=3):
Mixed Media: 98%
Heparin Only: 0%
* Lipopolysaccharide© ExThera Medical 4/13
Mixed Media
Heparin-Only
SEMs After Blood Contact
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Media Synthesis and Drying:
Automated Manufacturing of Seraph Columns:Optimized for Specific Diseases or Very Broad Spectrum Use
Heparin Media 3Media 2 (Media 4?)
Order Blend & Quantity Automated
Blending
and Filling
Filled
Seraph
Column
0.E+00
1.E+05
2.E+05
3.E+05
4.E+05
5.E+05
6.E+05
7.E+05
8.E+05
9.E+05
1.E+06
MRSA+CRE
CRE
MRSA
Independent Binding Studies - Bacteria Removed SeparatelyStarting Concentration
(CFU/ml)Ending Concentration
(CFU/ml)% Reduction CFU/g
MRSA 1.21E+05 1.02E+04 92% 3.69E+05
K. pneumoniae (CRE) 1.40E+05 7.83E+01 99.9% 4.66E+05
Total CFU/g expected if tested simultaneous without binding competition 8.36E+05
Polymicrobial Study - Bacteria Removed SimultaneouslyStarting Concentration
(CFU/ml)Ending Concentration
(CFU/ml)% Reduction CFU/g
MRSA 2.03E+05 3.52E+04 83% 5.59E+05
K. pneumoniae (CRE) 2.07E+05 1.12E+05 46% 3.17E+05
Total CFU/g (MRSA + K. pneumoniae) 8.76E+05
Polymicrobial Binding Does Not Change Capacity of Seraph Media
Conclusion: Competitive binding is negligible.
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Seraph® Animal Safety Study (During Dialysis)
Catheter Placement Filling While Displacing Saline
Experiment In Progress Rinsed Column at 3.5 hrs.©ExThera Medical 4/14
Conclusion
The Seraph® Microbind® Affinity Blood Filter (Seraph) uses ExThera’s proprietary biomaterials (adsorption media) to create a device that fills a large and growing clinical need
• A safe, broad-spectrum treatment of bloodstream infections caused by increasingly drug-resistant organisms
• Captures pathogens and toxins to reduce the inflammatory response and stop the progression of BSI to sepsis, severe sepsis and septic shock
• Reduces healthcare costs by avoiding expensive ICU care
• Addresses several very large markets• Therapeutic: Bloodstream Infections / Sepsis
• Prophylactic: Blood Banking
Confidential
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• 99.8% of herpes simplex virus 1
• 80% of TNF-α cytokine in one hour 5
Bacteria, Toxins, Viruses and Pro-inflammatory Cytokines
• 85% of MRSA bacteria in single pass 1,2,3
• 100% of S. aureus α-toxin in a single pass 2
• > 99.9% of E. coli, Klebsiella pneumoniae
(‘CRE Super Bugs’) 3
• 85% of Pseudomonas aeruginosa 3
• 98% of Endotoxin 4
Independently Tested
Collaborators
Centers:1 University of Gothenburg, Sweden
2 Texas A&M, USA
3 Antimicrobial Test Labs, USA
4 Ludwig Boltzmann Institute, Austria
5 University of Minnesota, USA
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