1. Ramon Quesada, MD, FACP,FACC, FSCAI
Design Update of NMT for PFO Closure
2010
Ramon Quesada, MD, FACP,FACC, FSCAI
Medical Director, Interventional Cardiology
Baptist Cardiac & Vascular Institute
Miami, Florida

2. Ramon Quesada, MD DISCLOSURES
I have no real or apparent conflicts of interest to report.

3. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship Company
Grant/Research Support None
Consulting Fees/Honoraria Abbott, Cordis, St. Jude, W.L. Gore, NMT Medical, Terumo & Boston Scientific Corporation
Major Stock Shareholder/Equity None
Royalty Income None
Ownership/Founder None
Intellectual Property Rights None
Other Financial Benefit None

4. The Clinical Dilemma PFOs exist in about 25% of the population
There are two major indications for PFO closure
Cryptogenic Stroke
Migraine
Other conditions potentially linked to PFO
Dementia
Alzheimer’s
Decompression illness in divers
Perioperative Hypoxemia
Pulmonary Embolism
Chronic Obstructive Pulmonary Disorder (COPD)
Obstructive Sleep Apnea
Transient Global Ischemia 4

5. The NMT Devices CardioSEAL® STARFlex® BioSTAR® BioTREK™ Permanent
Partially or Completely Bioabsorbable
BioSTAR®
BioTREK®

6. CardioSEAL® Long history of use (>22,000 implanted)
FDA approved for PFO (via HDE) until 2006; current FDA approval for high risk VSD’s
MP35n frame for excellent corrosion resistance & polyester fabric for proven endothelialization
98% closure rate documented in PFOs1; 80% in ASDs2
Catheter Cardiovasc Interv 2006; 68(1):
J Am Coll Cardiol 2006; 48:538–44.

7. STARFlex® CE Mark since 1998 (>6,000 implanted)
IDE studies in US for ASD and PFO (CLOSURE I) & OUS Migraine Trial (MIST)
CardioSEAL® frame with addition of a PFO-compatible nitinol centering mechanism
improves conformability in difficult anatomy
94% closure rate documented in PFOs1; 93% in ASDs2
Circulation 2008; 117:
J Am Coll Cardiol 2006; 48:538–44.

8. Anatomical Issues: Device Solutions

9. Anatomical Challenges
Long tunnel > 16 mm
Large septal aneurysm with eccentric tunnel
Fenestrated atrial septum

10. Anatomical Challenges
Long tunnel > 16 mm
Large septal aneurysm with eccentric tunnel
Fenestrated atrial septum

11. 29 mm PFO channel

12. Measurement 29 mm PFO channel+ +

13. Transeptal Puncture –29 mm PFO channel

14. Closure with 33mm CardioSEAL®

15. Important Tip: For a long channel (> 16 mm) with or for a large associated ASA consider trans-septal puncture to avoid “confining” of the right atrial component of the device within the channel

16. Confined right atrial component within channel
Case 2a
Confined right atrial component within channel

17. Case 2a
Post release right atrial component confined  snared to properly reposition the device

18. Anatomical Challenges
Long tunnel > 16 mm
Large septal aneurysm with eccentric tunnel
Fenestrated atrial septum

19. Case 2
Large ASA
Cut to section where > appears--done

20. Catheter through Fenestration
Case 2
Catheter through Fenestration
Trnaspeptal with circle make it into short film

21. Catheter through Fenestration
Case 2
Catheter through Fenestration
Trnaspeptal with circle make it into short film

22. Closure with 33mm CardioSeal® with Stabilization of ASA
Case 2
Closure with 33mm CardioSeal® with Stabilization of ASA
Launez transeptal

23. PFO Repair via Transseptal Puncture
28/255 (10.9%) PFO Procedures used transseptal puncture technique
Overall mean channel length 14.4 mm
PFO/ASA n= 13 Mean Channel 14.7
PFO n= 15 Mean Channel 14.4
Results : 100% success with no shunts and no complications

24. New Technology BioSTAR® Bioabsorbable Tissue-engineered
Collagen Matrix
BioTREK™ Bioabsorbable Biosynthetic Polymer

25. Why bioabsorbable? less risk of long term complications
potential to regenerate functional tissue
allow future interventions
improved MRI imaging
avoidance of chronic foreign body reaction1
patient preference
1. Heart 2006;93(4):444-9

26. BioSTAR®
First use of bioabsorbable material for structural heart repair
Novel Features 
Real Clinical benefits1
Rapid endothelialization
-High early closure rates
-Reduced risk of thrombosis
Regeneration of native-like septum
-Improved potential for LA access later in life
1. Circulation 2006; 114:1962-7

27. BioSTAR® Implant Design
Tissue-engineered collagen matrix derived from the submucosal layer of the porcine small intestine (ICL) (Organogenesis Inc., Canton, MA)
close hole acutely
function as a “bioremodeling” template for the ingrowth of host cells
Proven STARFlex® framework
Heparin coating
CE Mark since 2007 (>2,000 implanted)

28. BioSTAR® Septal Repair Implant

29. BioSTAR® Pre-clinical Findings
Compared to STARFlex® (control), the BioSTAR® showed an accelerated healing response
First signs of a single-layer neo-endothelium were observed already after 7 days in vivo
Heparin coating of the BioSTAR® surface reduced surface thrombogenicity
The ICL collagen matrix exhibited a surprisingly low immune response
J Am Coll Cardiol 2006; 48:161-9

30. BioSTAR® Remodeling
Absorption was approximately 90% complete at 2 years with no fibrous capsule formation
30 days
2 years
J Am Coll Cardiol 2006; 48:161-9

31. Comparative Healing Response
30d
180d
STARFlex®
BioSTAR®
At both time periods, BioSTAR® demonstrated more extensive tissue encapsulation and better sealing to the atrial wall as compared to STARFlex®
Photos courtesy of Dr. Christian Jux, University of Goettingen/Germany and
Dr. Peter Wohlsein, Institute of Pathology, School of Veterinary Medicine Hannover/Germany

32. Comparative Thrombogenicity
STARFlex®
ICL no heparin
BioSTAR®
After 7 days, the heparin coated BioSTAR® showed lower levels of
plasma protein deposition than STARFlex® and an uncoated BioSTAR®
Photos courtesy of Dr. Christian Jux, University of Goettingen/Germany and
Dr. Peter Wohlsein, Institute of Pathology, School of Veterinary Medicine Hannover/Germany

33. BioSTAR® Evaluation Study (BEST) Clinical Trial
Follow-up
ASA 75mg OD; Clopidogrel 75mg OD for 3 months
Contrast TTE at baseline, 30 days and 6 months
TEE at implant and 30 days
Studies reviewed by echo core lab
Inflammatory markers at baseline, 30 days and 6 months
Slide courtesy M Mullen, Royal Brompton, London, UK

34. BEST Results N % N % 57/58 patients successfully had a BioSTAR implant
Closure at 30 days 48/52 92
Closure at 6 months 54/56 96
Safety – No major safety issues:
N %
Atrial arrhythmia % resolved
Urticuria % resolved
RA echogenic mass % resolved
Slide courtesy M Mullen, Royal Brompton, London, UK

35. BioSTAR® Evaluation Study (BEST) Immunological Markers
HS-CRP
ESR
mg/dl
mm/hr 32
136 31 48 26 14 14 12 12 10 10 8 8 6 6 4 4 2 2 BL 4 12 26 BL 4 12 26
weeks
weeks
Slide courtesy M Mullen, Royal Brompton, London, UK

36. BioSTAR® Advantages
High closure rates in wide range of PFO defect morphologies
30d; 6 mos. (Mullen 2006)
No PFO patients excluded due to anatomy
Long tunnel, ASA, thick septum secundum
90-95% bioabsorbable
Regenerates native-like septum (Jux 2006)
Potential for future LA access
Low thrombogenicity
Heparin coated
Rapid endothelialization (Jux 2006)
Simple to use
With RT delivery system:
Free implant/delivery system interface

37. BioTREK™ Bioabsorbable Septal Repair
100% absorption over time
Novel bioabsorbable polymer (P4HB)
absorbs as a non-inflammatory natural metabolite
Easily repositionable and retrievable
Radiopaque and echogenic
Currently in pre-clinical studies
P4HB stands for poly-4-hydroxybutyrate
It breaks down to form 4-hydroxybutyric acid
6 months
Explant photo courtesy of Aaron V. Kaplan, MD and Ebo D. de Muinck, M.D. Ph.D., Dartmouth Medical School (USA)

38. BioTREK™: Polymer (P4HB)
Novel biomaterial received 1st FDA clearance 2007 (sutures/meshes)
Biologically produced
isolated from bacteria modified by recombinant DNA technology1
no residual metal catalysts
More flexible & less inflammatory than currently available bioabsorbables
P4HB in
recombinant bacteria
Production by biological fermentation has value because such materials do not contain residual metal catalysts such as those used in chemical synthesis (which can cause inflammation)
1. Biochemical Engineering Journal 2003;16:97-105
Photo courtesy Tepha, Inc.

39. BioTREK™ Key Design Goals
complete closure within 30d
no permanent foreign material
easily retrievable & repositionable
no change to current procedure
radiopaque & echogenic
conformable and atraumatic
low thrombogenicity
intuitive delivery
effective in most shapes/sizes of PFO’s
You should be aware that BioTREK, in its current configuration, is a PFO specific design – smaller LA side than RA which helps with achieving good apposition in a double disc design (unlike an umbrella where the legs can be “crossed” before deployment). We do have ASD specific concepts as well.

40. BioTREK™ Implant PFO Specific Design: LA side < RA side Frame
You should be aware that BioTREK, in its current configuration, is a PFO specific design – smaller LA side than RA which helps with achieving good apposition in a double disc design (unlike an umbrella where the legs can be “crossed” before deployment). We do have ASD specific concepts as well.
Scaffold

41. Preclinical: ICE Imaging
ICE image at implant showing good aposition to heart wall in pig model.
FYI - typically use sheep for all our healing studies but happened to be doing an acute study here.

42. Preclinical: Fluoroscopic Imaging
Fluoro image at implant in pig model.
FYI - typically use sheep for all our healing studies but happened to be doing an acute study here.

43. Gross Images: 1 Month RA LA
Pre-clinical testing of BioTREK was conducted using the sheep model (female sheep 5-6 months old)
Defect creation was done using Brockenbrough technique and a non-compliant balloon {12mm 12 atm (3 x 30 sec)}
Device implantation occurred 2 weeks later RA LA

44. Gross Images: 6 Months RA LA
Here we have 6 month gross and histology images from the animal model. As you can see, the device is well healed with granulation tissue, mainly fibrosis (fibroblasts and collagen). RA LA

45. Histology: 1 Month At 1 mo:
-well healed with granulation tissue, mainly fibrosis (fibroblasts and collagen)
-apparent endothelial cell coverage on surface
-a very low inflammatory response
-although very little resorption of the material

46. Histology: 6 Months Strut Scaffold And at 6 mo:
-resorption continues as confirmed through MW loss
-foreign body response is still low which is promising although longer term data is needed
Note: minimal or no focal chronic inflammation seen at 6 months

47. Summary In preclinical studies, BioTREK™ has achieved:
No permanent foreign material
Easily retrievable & repositionable
No change to current procedure
Radiopaque & echogenic
Minimal chronic inflammation
BioTREK™ has the potential to achieve effective closure without chronic inflammation or permanent implant
Status:
Current focus is continuing to optimize the design including improving ease of use, healing rate, and conformability
Next step will be to conduct our pivotal animal study
Timing is TBD
ask Frank what he wants to say here - hopefully we will start pivotal animals sometime in 2010 and then a human clinical trial could start approximately mos. later

48. International Symposium on Endovascular Therapy
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January, 2011
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