WO2018029166A1 - Procédé de revêtement d'un dispositif médical, en particulier d'une endoprothèse vasculaire - Google Patents

Procédé de revêtement d'un dispositif médical, en particulier d'une endoprothèse vasculaire Download PDF

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Publication number
WO2018029166A1
WO2018029166A1 PCT/EP2017/070007 EP2017070007W WO2018029166A1 WO 2018029166 A1 WO2018029166 A1 WO 2018029166A1 EP 2017070007 W EP2017070007 W EP 2017070007W WO 2018029166 A1 WO2018029166 A1 WO 2018029166A1
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WO
WIPO (PCT)
Prior art keywords
nanotubular
titanium
matrix
vascular stent
oxygen atoms
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PCT/EP2017/070007
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English (en)
Inventor
Mukta KULKARNI
Ita Junkar
Aleš IGLIC
Janez KOVAC
Miran Mozetic
Original Assignee
Jožef Stefan Institute
University Of Ljubljana
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Jožef Stefan Institute, University Of Ljubljana filed Critical Jožef Stefan Institute
Priority to EP17758070.1A priority Critical patent/EP3496776A1/fr
Publication of WO2018029166A1 publication Critical patent/WO2018029166A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • the present invention relates to a method for coating a vascular stent and to a vascular stent preferably produced by said method.
  • stent is a mesh 'tube' inserted into a natural passage in the body to prevent or counteract a disease-induced, localized flow constriction and to allow open access for surgery.
  • clumping or aggregation of platelets in the blood leads to the formation of a thrombus (clot).
  • This thrombosis formation of thrombus
  • obstructs the flow of blood through the circulatory system which leads to cardiovascular disease and increases risk of heart attack and strike' as disclosed in "Coronary Artery Disease, Angina, and Heart Attacks.” in Texas Heart Institute Heart Owner's Handbook.
  • thrombosis leads to serious short-term and long-term effects.
  • a possible short-term effect is pulmonary embolism, in which the blood clot breaks into pieces, travels to the lungs and blocks the flow of blood through the lungs.
  • Such effects are disclosed for instance in Bernardi E and Prandoni P., the post-thrombotic syndrome, Current Opinions in Pulmonary Medicine 2000, volume 6: pages 335-42. and Janssen MCH et al., The post- thrombotic syndrome: a review, Phlebology 1996; volume 1 : pages 86-94.
  • Coronary artery disease presents the major cause of mortality in the modern world.
  • the majority of percutaneous coronary interventions involve stents, which are implemented in order to help enlarge the lumen wall and restore the blood flow through the affected vessel.
  • Stents are made of hemocompatible and durable material such as titanium (Ti), 316L stainless steel (SS-medical grade), Nitinol (an alloy of Nickel and Titanium) and Cobalt- Chromium (CoCr).
  • a stent can elicit allergic reactions most commonly those that are containing Nickel, such as Nitinol and stainless stee as shown in "Cutaneous and Systemic Hypersensitivity Reactions to Metallic Implant", Juliana L. Basko-Plluska, Jacob P. Thyssen, Peter C.
  • stent restenosis As described in "Repeat Narrowing of a Coronary Artery Prevention and Treatment", George Dangas, MD; Frank Kuepper, MD Circulation. 2002; 105: 2586-2587. Restenosis is defined as 50% narrowing of vessels diameter and still to this day remains a major problem. In more than 33% of cases restenosis will occur, with higher possibilities in patients with high risk factors, such as diabetes.
  • BMS bare metal stents
  • DES drug- eluting stents
  • Procedures and methods for coating stent surfaces are mainly accomplished by various polymeric coatings ("Polymer Coatings for Stents", Tim A. Fischell, MD, Circulation. 1996; 94: 1494-1495) or nanocrystalline powders of ceramics, such as hydroxyapatite, titanium dioxide, by plasma thermal sprays or coating of noble metal oxides (cf. US 567815, US 6099561 , US 6478815) or by covering surface with bioactive coatings like heparin, chitosan, fibronectin etc. (cf. CA1257561 , US3617344, WO2003070125, WO1996008149, WO2000040278).
  • coated surfaces are not a satisfactory solution, as coated stents cause blood clots several years after implementation shown in Brian Vastag's, "Stents Stumble", Science News, Jun 23, 2007 vol.171 , pp 394-395. Moreover patients with coated stent must receive blood thinners all their lives in order to prevent the risk for stroke or heart attack.
  • the probability of death by cardiac infarction in the period of 6 months to 3 years after implementation of DES is 32% higher than on BMS as described by Lagerqvist B. et al., Long term outcomes with drug eluting stents versus bare metal, New England Journal of Medicine 2007, 356, 1009-1019.
  • Success of stents depends mainly on avoiding the aggregation of platelets in the blood vessels as well as to prevent uncontrolled proliferation of smooth muscle cells and appropriate proliferation of endothelial cells.
  • Research in the field of nanomaterials has revealed that the topography is a crucial factor for appropriate biological response and the need to produce such surfaces for desired biological response could be the solution.
  • WO2014087414 a method for preparing biocompatible metallic surfaces by nanostructuring is disclosed.
  • the nanostructuring involves hydrothermal treatment in alkaline conditions at elevated temperatures by which superior endothelization with reduced smooth muscle cell proliferation and platelet adhesion is achieved.
  • non-toxic chemicals are used at varying temperatures in order to yield distinct nanostructure, such as rods, pins, needles, pores etc.
  • the method used to produce such nanostructures is different from our approach and the produced nanostructures differ from the ones produced by our method in size and shape.
  • the material surface is essentially of titanium oxide (T1O2) with hydrophilic properties which enable improved protein interaction and enhance adhesion and proliferation of endothelial cells, while reducing adhesion of smooth muscle cells, platelets and monocytes.
  • Nanostructures allow adhesion and growth of one cell type, for example endothelial cells to smooth muscle cells. This is achieved by pattering the substrate to have an organized structure. The pattern is obtained by layering nanostructure material at least partially over the substrate and producing alternating layers of different nanostructure material which forms a patterned layer and in the end etching the surface to form desired nanostructure.
  • the surface consists of oxide metal layer which has nanotubues with pore diameter between 15 to 100 nm and height of the tube between 15 to 5000 nm.
  • the nanotubes are formed on metal containing surface by electrochemical anodization and the surface is further annealed at a temperature between 280 to about 580° C.
  • Such surface is appropriate for bone implants, stents, drug depot and fusion cage.
  • the main difference between the methods used in their patent is that different electrochemical anodization process is employed (different electrolyte) and that nanotubular array is further annealed, while in our case after electrochemical anodization surface is treated with neutral oxygen atoms.
  • the nanotubular array produced by our method of invention is not stable at high temperatures and the surface could not be annealed.
  • the temperatures are well below 150° C.
  • US201 10236435 discloses the method of growing bone cells on T1O2 nanotubular substrates treated by plasma.
  • the titanium substrate is anodized to form T1O2 nanotubular array which is afterwards subjected to a radiofrequency plasma discharge to chemically modify the array and to seed bone cells for effective time to enable growth of these cells.
  • the RF discharge is used at the pressure of 20 Pa in several gases: nitrogen, oxygen, a mixture of nitrogen and oxygen and helium.
  • the preferred length of nanotubes to facilitate bone cells growth is 4 mm and preferred inner diameter from about 80 to 107 nm. Best results are obtained by treatment with plasma created in mixture of nitrogen and oxygen. This is primarily due to formation of nitrogen and oxygen based functional groups which promote cell growth and adhesion.
  • the technical problem of the present invention is providing reduction of adhesion of platelets on implantable medical devices.
  • a method of coating a vascular stent comprises: Providing a vascular stent with at least one metal surface, in particular a titanium based surface, Forming a nanotubular matrix, wherein said nanotubular matrix comprises metal oxide, in particular titanium dioxide, said formed nanotubular matrix having predetermined dimensions formed by anodizing said metal surface in an electrochemical manner and Subjecting said formed nanotubular matrix to neutral oxygen atoms in order to remove impurities from the surface obtained during electrochemical anodnization, predominantly fluorine and nitrogen, and to increase oxygen concentration on nanotubular array.
  • nanostructuring can be obtained from titanium or metal alloys of titanium on a surface. It may also be metal surfaces consisting of titanium, titanium alloys, stainless steel alloys, cobalt based alloys, cobalt-chromium alloys or the like.
  • nanotubular matrix By subjecting said nanotubular matrix to neutral oxygen atoms removal of undesired chemicals that are adsorbed to the surface due to electrochemical process is provided. Moreover such treatment (that is subjecting to neutral oxygen atoms) increases oxygen content on the surfaces and a higher quality oxygen surface layer is formed, which plays an important role in biological response.
  • nanotubular matrix or “array” refers to a nanotube structure which is aligned vertically to the substrate or metal surface (titanium material) and where the nanotubes are uniformly or homogenously distributed.
  • the method of invention enables appropriate surface conditioning, which highly reduce adhesion and activation of platelets.
  • the method involves 1.) nanostructuring the surface of titanium by electrochemical anodization and 2.) subjecting the nanostructured surface to neutral oxygen atoms to eliminate surface induced thrombotic reactions.
  • Electrochemical anodization represents an optimum method for obtaining nanostructures, due to its good control over nanotubular morphology and ease of application. While appropriate chemical properties can be achieved by treatment of titanium dioxide nanotubes with neutral oxygen atoms.
  • the first event taking place immediately after stent implantation is adsorption of blood proteins at the implant- liquid interface. The amount and type of adsorbed protein further influences the success of implant.
  • the adsorbed protein layer governs interaction of platelets and their adhesion or activation, leukocyte recruitment, activation of intrinsic coagulation and of complement; moreover, all four are capable of eliciting a thrombogenic response in vivo.
  • the adsorbed protein layer will lead to adhesion and activation of the platelets, which is fundamental in forming the fibrin clot and recruiting leukocytes (as monocytes and neutrophils).
  • the platelets will trigger an inflammatory immune response which would lead to either thrombosis and/ or fibrous encapsulation of the implant.
  • less thrombogenic effects with lower surface induced fibrin clot formation were registered on nanotubes in comparison to titanium surfaces. The latter was evident from slightly decreased levels of complement activation and slightly increased degree of free fibrinogen on nanotubular surfaces.
  • One aspect of the present invention is that appropriate techniques are used to produce endovascular metallic device (stent) that prevents adhesion and activation of platelets on the surface simply due to nanostructuring (appropriate size of nanotube diameter and its length) and chemical modification of the surface using only neutral oxygen atoms in the absence of plasma-generated species such as ions and electrons.
  • the desired nanostructured array or matrix, respectively is obtained by electrochemical anodization.
  • Chemical modification is obtained by subjecting the array to neutral oxygen atoms which remove chemical impurities induced by anodization procedure and produce denser oxygen layer which highly reduces adhesion and activation of platelets on the surface. It also causes removal of nitrogen and carbon that is typically present on the surface of titanium.
  • titanium nanostructured surfaces produced by the present method of invention have appropriate chemical structure and topography which reduces the risk of thrombosis on blood contacting devices.
  • the final sterilization step should be considered.
  • H2O2 or O2 plasma or even gamma sterilization should be employed.
  • Other currently available sterilization techniques result in altered surface morphology and chemistry, which influences on the biological response.
  • sterilization with autoclave is not appropriate as the nanostructured morphology could be destructed and the content of carbon functional groups is undesirably increased.
  • the surface is interacting with neutral oxygen atoms, similar to the previously described treatment step by neutral oxygen atoms, thus preventing changes in surface morphology and chemistry.
  • Gamma irradiation sterilizes the surface by high ionized energy and will not alter nanotubular array morphology nor it will significantly alter the surface chemistry.
  • subjecting of said nanotubular matrix at fluencies in the range of 10 22 to 10 25 nr 2 is provided. Due to subjecting of the nanotubular matrix or array to neutral oxygen atoms removal of impurities, such as fluorine, carbon and nitrogen is prodded. Additionally the oxygen concentration on the surface is increased, which prevents adhesion and activation of platelets to the surface.
  • Fig. 1 shows a SEM image of nanotube arrays with 100nm in diameter- from top view (Scale bar is 500nm) according to the present invention
  • Fig. 2 discloses a SEM image of nanotube arrays with 100nm in diameter- cross section view
  • Fig. 3 shows the surface morphology of nanotubular array obtained by atomic force microscopy (AFM) on surfaces produced by the method of invention
  • Fig. 4 Schematic representation of platelet interacting with; plain titanium foil, titanium nanotubular array surface and titanium nanotubular array surface produced by the method of invention;
  • Fig. 5 shows the anodization conditions for nanotubes with 100nm diameter and 3.7 ⁇ length (sample name shows: sample name, diameter, and length of nanostructures respectively), EG: Ethylene glycol, HF: Hydrogen fluoride; Fig. 6 depicts measured values of chemical groups by ESCA (Electron Spectroscopy for Chemical Analyses) on the surface of plain titanium, nanotubular array of ⁇ 2 and nanotubular array of ⁇ 2 subjected to natural oxygen atoms; Fig. 7 shows adhesion and activation of platelets on plain titanium; and
  • Fig 8 discloses adhesion and activation of platelets on nanotubular array of ⁇ 2 subjected to neutral oxygen atoms according to the present invention.
  • a method according to the invention for surface finish of titanium based implants in contact with blood prevents adhesion and activation of platelets against the state of the art is disclosed.
  • the present invention comprises of a.) electrochemical anodization of titanium surface and formation of an nanotubular array of titanium dioxide with desired diameters and lengths, b.) subjecting the electrochemically anodized titanium dioxide nanotubular array to neutral oxygen atoms to remove impurities from the surface obtained during electrochemical adonization, predominantly fluorine and nitrogen, and to increase oxygen concentration on nanotubular array.
  • the surface of titanium substrate is electrochemically anodized only in single ethylene glycol based electrolyte with specific amount of deionized water and hydrogen fluoride as an additive for etching the titanium surface.
  • Obtained T1O2 nanotubular arrays are of desired diameters ranging from 15 nm to 100 nm inner diameters and lengths varying from 370 nm to 3.7 ⁇ .
  • the expression "nanotubular array” refers to a nanotube structure which is aligned vertically to the substrate (titanium material) and where the nanotubes are uniformly distributed as presented in Figure 1 -3.
  • Obtained nanotubular array is subjected to neutral oxygen atoms at fluencies, in the range of 10 22 to 10 25 nr 2 .
  • nanotubular arrays to neutral oxygen atoms removes impurities, such as fluorine, carbon and nitrogen and increases the oxygen concentration on the surface, which prevents adhesion and activation of platelets to the surface, as schematically presented in Figure 4.
  • Example 1 plain titanium
  • plain titanium was analysed by ESCA method in order to obtain information about chemical composition of the surface. Results of chemical composition are presented in Figure 5.
  • the adhesion and activation of platelets on plain titanium foil was done according to the following procedure; prior to whole blood incubation plain titanium surfaces were cleaned with ethanol, dried and incubated with whole blood taken by vein puncture from a healthy human donor Titanium foils were incubated for 1 hour with whole blood.
  • the blood was drawn into 9 ml tubes with tri sodium citrate anticoagulant (Sigma). Afterwards the fresh blood was incubated with titanium surfaces in 24 well plates for 1 hour at room temperature and at gentle shaking at 300 RPM. Each sample (measuring 13 mm in diameter) was incubated with 1 ml of whole blood.
  • PBS phosphate-buffered saline
  • the surfaces were rinsed with PBS and then dehydrated using a graded ethanol series (50, 70, 80, 90, 100 and again 100 vol.% ethanol) for 5 min and in the last stage in the series (100 vol.% ethanol) for 15 min.
  • the samples were placed in a Critical Point Dryer, where the solvent is exchanged with liquid carbon dioxide. By rising the temperature in the drier the liquid carbon dioxide passes the critical point, at which the density of the liquid equals the density of the vapour phase. This drying process preserves the natural structure of the sample and avoids surface tension which could be caused by normal drying.
  • the dried samples were subsequently coated with gold and examined by means of SEM (Carl Zeiss Supra 35 VP) at accelerating voltage of 1 -keV.
  • Example 2 growth of nanotubes and platelet adhesion and activation
  • Titanium dioxide nanotubular arraytitanium with 100 nm in diameter was obtained by electrochemical anodization of titanium foils (Advent, 0.1 mm thickness, 99.6% purity). Prior to anodization, titanium foils were degreased by successive ultrasonication in acetone, ethanol and deionized (Dl) water for 5 min each and then dried in nitrogen stream. Nanotubes with diameter 100nm and 3.7 ⁇ lengths were obtained in ethylene glycol based electrolyte containing 8M water and 0.2M hydrogen fluoride. Anodization voltage was set to 58V for 2.5h to get desired diameters and lengths of nanotubes.
  • Example 3 growth of nanotubes by the method of invention and platelet adhesion and activation
  • Titanium dioxide nanotubular array with 100 nm in diameter was obtained by electrochemical anodization of titanium foils according to the procedure described in Example 2.
  • Dried T1O2 nanotubular arrays were mounted into the treatment chamber and were treated only by neutral oxygen atoms in the absence of plasma-generated species such as ions and electrons.
  • the fluence of natural oxygen atoms was about 2x10 22 nr 2 .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Epidemiology (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un procédé de fabrication de la morphologie souhaitée d'une matrice nanotubulaire, en particulier d'une matrice contenant du dioxyde de titane, qui réduit l'adhérence et l'activation de plaquettes sur des dispositifs médicaux. Les surfaces fabriquées selon le procédé de l'invention peuvent être utilisées pour des dispositifs de mise en contact avec le sang, tels que des endoprothèses vasculaires et des valvules cardiaques artificielles, afin de réduire les réactions entraînant la formation de caillots sanguins sur la surface du matériau de l'implant.
PCT/EP2017/070007 2016-08-09 2017-08-08 Procédé de revêtement d'un dispositif médical, en particulier d'une endoprothèse vasculaire WO2018029166A1 (fr)

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DE102016114699 2016-08-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4049690A1 (fr) * 2021-02-25 2022-08-31 Jozef Stefan Institute Procédé de traitement de métaux médicaux et leurs alliages
EP4129351A1 (fr) 2021-08-05 2023-02-08 Jozef Stefan Institute Procédé de production de surfaces nanostructurées sur des endoprothèses pour une biocompatibilité améliorée

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WO1996008149A1 (fr) 1994-09-16 1996-03-21 Beatrice Haimovich Traitement de surface thromboresistant pour biomateriaux
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US6099561A (en) 1996-10-21 2000-08-08 Inflow Dynamics, Inc. Vascular and endoluminal stents with improved coatings
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4049690A1 (fr) * 2021-02-25 2022-08-31 Jozef Stefan Institute Procédé de traitement de métaux médicaux et leurs alliages
EP4129351A1 (fr) 2021-08-05 2023-02-08 Jozef Stefan Institute Procédé de production de surfaces nanostructurées sur des endoprothèses pour une biocompatibilité améliorée

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