and Bio Absorbables John Wainwright PhD Sr RampD Manager Medtronic plc WLNC 060815 Some of the technologiesdevices discussed in this talk are not approved in the US Reasons for Coatings and Surface Modifications ID: 775616
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Slide1
Coatings, Surface Modifications, and Bio-Absorbables
John Wainwright, Ph.D.Sr. R&D Manager, Medtronic plc
WLNC 06/08/15
Some of the technologies/devices discussed in this talk are not approved in the US
Slide2Reasons for Coatings and Surface Modifications
Lubricious coatings
Hydrophobic
Hydrophilic
Corrosion Resistance
Material Choice
Stainless steel,
CoCr
,
NiTi
Passivation
Electropolish
Parylene
coating
Lower material
thrombogenicity
Electropolishing
Silicon Carbide
Heparin
Phosphoryl
Choline
Bio-Absorbable stents
Slide3Lubricious Coatings
Extremely dependent on processing conditions including: cleaning, activation/base coat, coating, curingTesting:Water droplet contact angle for hydrophilicityFriction for lubricity and durabilityParticulate testing for durability/device interactions
HydrophobicPTFE (fluoropolymers): longest useInert but higher friction than PVP and HAHydrophilicHydroscopic (swell in fluid)PVP (polyvinylpyrrolidone): Most common hydrophilicPVP particles from Cook Shuttle/Slip-Cath has been associated with intraparenchymal hemorrhage in 3 patients (Hu et al 2014) HA (hyaluronic acid): more lubricious/biocompatible, but less stable
Slide4Corrosion Resistance
Material ChoiceStainless steel, CoCr, NitinolCoCr more corrosion resistant without post processing due to compositionNiti corrosion resistance (Trepanier 97)PA=PassivatedEP= ElectropolishedHT= Heat treatedAA= electropolished and then heat treatedNT= non-treatedParylene coating- polymer coating applied through vapor deposition often applied for corrosion resistanceEnterprise™ device is covered with a thin layer of Parylene (Heller 2011)“Lubricious Coating Our proprietary stent coating may facilitate stent tracking through the microcatheter.” (Codman marketing brochure)
Higher Breakdown
Potential (
Ebd
)= more corrosion resistant
Slide5Lower material thrombogenicity
Electropolishing
EP
NiTi
has shown to absorb less platelets and plasma than stainless steel (Thierry 2002)
Inert titanium oxide surface
Silicon
Carbide
Chemically inert, corrosion resistant, and may reduce
thombogenicity
(Harder
et al
99)
PHAROS
Viteese
ICAD stent and
Rithron
coronary stent
PhosphorylCholine
(PC)
PC
is naturally abundant on the surface of red blood
cells
1-10
Coating
or treating a device surface with a PC-containing polymer results in physiologic mimicry of the cell
membrane
Heparin
Actively prevents
thrombus formation so could affect aneurysm occlusion
BX
VELOCITY stent with HEPACOAT and aspirin alone after the procedure was safe in select patients with de novo or
restenotic
lesions in native coronary arteries.
(
Mehran
2003)
Carmeda
® heparin coating covalently bonded to surface
May
be regulated as a drug/combination product
Slide6PC Surface Modification vs. Coating
MethodShield Technology™ Surface Modification“Standard” PC Coating* Catheter or StentAdhesion to SubstrateCovalent Chemical Bonding Encapsulation Thickness< 3 nanometer(one braid wire=25400 nm)500-4000 nanometerProcessChemical ReactionDipping, Spray or BrushSEM ImagesBare BraidShield Technology™Early Development WorkEarly Development Work Early Development
*Note: Standard PC Coatings are similar to EVAHEART LVAD (ClinicalTrials.gov Identifier: NCT01187368), Endeavor (P060033) and BiodivYsio Stents (P000011)
Slide7Ways to evaluate thrombogenicity
Method
Pro
Con
aPTT
(partial thrombo
plastin
time)
Standard
biocompatiblity
and clinical
test
Not sensitive enough to detect differences
~5%
of thrombin is formed for clot time
Large
blood s
ample to sample variation
Blood flow loop testing
Visually stimulating results
Limited
number of samples per run
Large
blood s
ample to sample variation
Variation within test run
Animal models: Difficult
to titrate thrombogenic response. Safety Only
Porcine
Multiple devices per animal
More
pronounced endothelialization
More spasm
Rabbit
Possibly
more correlative aneurysm occlusion
Slower to
endothelialize
Elastase model has high morbidity, expensive, no internal controls
Slide8Material
Thrombogram Testing
Quantitative, Repeatable, Validated, method used clinically11-15Uses human platelets and plasma Compare Peak Thrombin (nM) More sensitive to differences than aPTT (industry standard)
Girdhar et al 2015
Slide9Testing Performed by Dr. Wayne Chandler, Director of Coagulation Laboratory Houston Methodist Hospital
Girdhar et al 2015 Bench Test results may not necessarily be indicative of clinical performance
Slide10Reduced Material Thrombogenicity
Virchow’s Triad of Thrombosis
Flow Disruption
Wall apposition
Stent design
Surface Activation
Intimal damageDevice material
HypercoagulableAnti-platelet non-responderHITOther
Shield Technology
™
only affects
Bench Test results may not necessarily be indicative of clinical performance
Slide11Bio-Absorable Stents
Abbott BVS most researched absorbable stent (ABSORB study)Thicker stent strutsHarder for deliveryMore issues with malapposition and overexpansion than metal stents7% malapposition Rate of absorption varies ~2 yrs for Abbott Absorb BVS
http://www.cathlabdigest.com/articles/Bioabsorbable-Stents-%
E2%80%93-Where-Are-We-Now
Slide12Future of innovation
Access and delivery systems: more lubricious and durable coatings
Flow Diverters and AB Stents: lower
thrombogenic
and enhanced
endothelialization
without perforator complications
Intrasacular
devices:???
Intracranial artery stenosis: address major complications of stroke and hemorrhage
Slide13References
Lewis, A.L. and P.W. Stratford,
Phosphorylcholine
-coated stents. J Long Term
Eff
Med Implants, 2002. 12(4): p. 231-50.
Lewis, A.L., et al.,
Crosslinkable
coatings from
phosphorylcholine
-based polymers. Biomaterials, 2001. 22(2): p. 99-111.
Whelan, D.M., et al., Biocompatibility of
phosphorylcholine
coated stents in normal porcine coronary arteries. Heart, 2000. 83(3): p. 338-45.
Kuiper, K.K., et al.,
Phosphorylcholine
-coated metallic stents in rabbit iliac and porcine coronary arteries.
Scand
Cardiovasc
J, 1998. 32(5): p. 261-8.
Chen, C., et al.,
Phosphorylcholine
coating of
ePTFE
grafts reduces
neointimal
hyperplasia in canine model. Ann
Vasc
Surg
, 1997. 11(1): p.
74-9.
Zheng
, H.
et al.
Clinical experience with a new biocompatible
phosphorylcholine
-coated coronary stent.
The Journal of invasive cardiology
11
, 608-614 (1999
).
Galli
, M.
et al.
Italian
BiodivYsio
open registry (
BiodivYsio
PC-coated stent): study of clinical outcomes of the implant of a PC-coated coronary stent.
The Journal of invasive cardiology
12
, 452-458 (2000
).
Grenadier
, E.
et al.
Stenting very small coronary
narrowings
(< 2 mm) using the biocompatible
phosphorylcholine
-coated coronary stent.
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions
55
, 303-308 (2002
).
Boland
, J. L.
et al.
Multicenter evaluation of the
phosphorylcholine
-coated
biodivYsio
stent in short de novo coronary lesions: The SOPHOS study.
International journal of cardiovascular interventions
3
, 215-225, doi:10.1080/14628840050515966 (2000
).
Beaudry
, Y., Sze, S.,
Fagih
, B., Constance, C. &
Kwee
, R. Six-month results of small vessel stenting (2.0-2.8 mm) with the
Biodivysio
SV stent.
The Journal of invasive cardiology
13
, 628-631 (2001
).
Chandler
, Wayne, and
Roshal
, Mikhail,
Optimization of Plasma
Fluorogenic
Thrombin-Generation Assays
, Am J
Clin
Pathol
2009; 132:169-179.
Gerotziafas
, et al.,
Towards a standardization of thrombin generation assessment: The influence of tissue factor, platelets and phospholipids concentration on the normal values of
Thrombogram-Thrombinoscope
assay
, Thrombosis Journal 2005, 3:16.
Hemker
, et al.,
Calibrated Automated Thrombin Generation Measurement in Clotting Plasma
,
Pathophysiol
Haemost
Thromb
2003; 33:4-15.
Spronk
, et al.,
Assessment of thrombin generation II: Validation of the Calibrated Automated
Thrombogram
in platelet-poor plasma in a clinical laboratory,
Thromb
Haemost
2008; 100:362-364.
Tepe
, G., et al.,
Thrombogenicity
of Various Endovascular Stent Types: An In Vitro Evaluation. Journal of Vascular and Interventional Radiology, 2002. 13(10): p. 1029-1035.