In vitro hemocompatibility of thin film nitinol in stenotic flow conditions

doi:10.1016/j.biomaterials.2010.08.014

Biomaterials

Volume 31, Issue 34, December 2010, Pages 8864-8871

https://doi.org/10.1016/j.biomaterials.2010.08.014 Get rights and content

Abstract

Because of its low profile and biologically inert behavior, thin film nitinol (TFN) is ideally suited for use in construction of endovascular devices. We have developed a surface treatment for TFN designed to minimize platelet adhesion by creating a superhydrophilic surface. The hemocompatibility of expanded polytetrafluorethylene (ePTFE), untreated thin film nitinol (UTFN), and a surface treated superhydrophilic thin film nitinol (STFN) was compared using an in vitro circulation model with whole blood under flow conditions simulating a moderate arterial stenosis. Scanning electron microscopy analysis showed increased thrombus on ePTFE as compared to UTFN or STFN. Total blood product deposition was 6.3 ± 0.8 mg/cm² for ePTFE, 4.5 ± 2.3 mg/cm² for UTFN, and 2.9 ± 0.4 mg/cm² for STFN (n = 12, p < 0.01). ELISA assay for fibrin showed 326 ± 42 μg/cm² for ePTFE, 45.6 ± 7.4 μg/cm² for UTFN, and 194 ± 25 μg/cm² for STFN (n = 12, p < 0.01). Platelet deposition measured by fluorescent intensity was 79,000 20,000 AU/mm² for ePTFE, 810 ± 190 AU/mm² for UTFN, and 1600 ± 25 AU/mm² for STFN (n = 10, p < 0.01). Mass spectrometry demonstrated a larger number of proteins on ePTFE as compared to either thin film. UTFN and STFN appear to attract significantly less thrombus than ePTFE. Given TFN’s low profile and our previously demonstrated ability to place TFN covered stents in vivo, it is an excellent candidate for use in next-generation endovascular stents grafts.

Introduction

Expanded polytetrafluorethylene (ePTFE) has been used for decades as an artificial conduit for vascular bypass grafts. More recently, it has become the most commonly used material for covering stents [1]. These covered stent grafts have been extremely successful at treating aneurysms of the thoracic and abdominal aorta and have dramatically decreased the need for large open surgical procedures [2], [3], [4]. As small diameter ePTFE covered stents have become available, their use has expanded to include treatment of atherosclerotic disease in the arteries of the pelvis and lower extremities. While ePTFE covered stents have shown some success in these smaller vessels, there are still significant technical challenges and limitations to their use. For example, restenosis rates for ePTFE are approximately 30% after 12 months, and this rate is known to increase as the length of the lesion being treated increases or as the diameter of the vessel decreases [5], [6], [7], [8], [9], [10]. Other disadvantages include a relatively rough surface, bulky delivery catheters double the size of those required for a comparable bare metal stents, and slow or non-existent endothelialization [11], [12], [13], [14], [15]. Therefore, there is an acute need to develop new biomaterials that are less thrombogenic, less bulky, and more easily endothelialized than the ePTFE currently used to cover stents.

Thin film nitinol (TFN defined as thickness less than 10 microns) is a nickel titanium alloy with a number of qualities that suggest it may be advantageous for use in blood contacting devices. Bulk nitinol (dimensions greater than 30 microns) has a long history of implantation in human beings and is currently the most common material used to manufacture stents due to its superelastic and temperature dependant shape memory properties. TFN retains the superelastic and shape memory properties indicative of bulk nitinol and also has a large tensile strength (500 MPa). TFN is manufactured in sheets between 1 and 10 μm thick with an average surface roughness of 5 nm as compared to surface roughness of most electropolished stents of 500 nm [16], [17], [18]. Its extremely low profile adds almost no bulk to the catheters used for endovascular delivery, and its smooth surface portends a favorable hemocompatibility profile as surface roughness is known to correlate with thrombogenicity [11], [12]. TFN may also be produced in a variety of shapes and sizes, and is not susceptible to the calcification commonly observed with ePTFE implants.

Previously, our group reported surface modifications to TFN that yielded a material with a contact wetting angle of 0° [18]. The “superhydrophilic” TFN (STFN) was designed to improve hemocompatibility as native endothelium is known to be both negatively charged and hydrophilic. Indeed, a recently published study of STFN showed dramatically decreased platelet adhesion and aggregation as compared to either ePTFE or untreated TFN (UTFN) [19]. The purpose of this study was to construct a more realistic model of the in vivo thrombotic response to TFN. We, therefore, developed an in vitro circulation model capable of circulating fresh whole blood under wall shear conditions simulating a moderate arterial stenosis. Using this model, we developed a series of assays to qualitatively and quantitatively examine experimentally formed thrombi. These techniques were then applied to prototype TFN covered stents with ePTFE covered stents serving as control.

Section snippets

Thin film nitinol creation

The fabrication process for TFN used in this study has been described in detail previously [20]. Briefly, the 6 μm thick films were deposited on a 4 inch silicon wafer buffered with a 500 nm silicon oxide layer. Following deposition and removal of the film from the silicon oxide layer, the film was crystallized for 120 min at 500 °C in a vacuum of less than 1 × 10⁻⁷ torr. The TFN material used for this study had an austenite finish temperature of approximately 34 °C. In all tests conducted in

Scanning electron microscopy

Qualitative analysis of scanning electron microscopy data showed markedly increased blood product deposition on ePTFE as compared to either UTFN or STFN. The deposited product was dense, making the morphology of individual components difficult to discern. In contrast, UTFN showed a markedly decreased density of blood product deposition. The deposit was composed of both fibrin and platelets with occasional red and white blood cells visible as well. STFN also showed markedly reduced blood product

Discussion

In this study we constructed an in vitro circulation model using whole blood to simulate the in vivo thrombotic response to thin film nitinol with ePTFE serving as control. For these studies, non-anticoagulated blood circulating at a wall shear rate similar to that found in a moderate arterial stenosis was used. An additional level of realism was added to our model by using prototype covered stents, as opposed to the bare material, because stents are known to cause local flow disturbances that

Conclusion

The purpose of this study was to compare the hemocompatibility profiles of ePTFE, UTFN and STFN in an in vitro circulation model using fresh whole human blood under conditions simulating a moderate arterial stenosis. A series of assays to qualitatively and quantitatively analyze the experimentally formed thrombi were developed. This data suggests that both forms of TFN tested attract significantly less thrombus than ePTFE under the highly thrombogenic experimental conditions. Our previous work

Acknowledgements

This work was supported by NIH challenge grant number 1RC1HL099445-01

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In vitro hemocompatibility of thin film nitinol in stenotic flow conditions

Abstract

Introduction

Section snippets

Thin film nitinol creation

Scanning electron microscopy

Discussion

Conclusion

Acknowledgements

J Am Coll Cardiol

J Vasc Surg

J Vasc Inter Radiol

J Vasc Interv Radiol

Eur J Vasc Endovasc Surg

J Vasc Surg

J Vasc Interv Radiol

Mater Sci Eng C

J Thin Solid Films

Biomaterials

Biomaterials

Biomaterials

Biomaterials

Biomaterials

Trends Biotechnol

J Vasc Interv Radiol

Biomaterials

Evolving modalities for femoropopliteal interventions

J Endovasc Ther

Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model

Health Technol Assess

Comparison of endovascular and open surgical repairs for abdominal aortic aneurysm

Endovascular stent-grafting in the treatment of superficial femoral artery occlusive disease

J Endovasc Ther