|Número de publicación||WO2014087414 A1|
|Tipo de publicación||Solicitud|
|Número de solicitud||PCT/IN2012/000788|
|Fecha de publicación||12 Jun 2014|
|Fecha de presentación||3 Dic 2012|
|Fecha de prioridad||3 Dic 2012|
|Número de publicación||PCT/2012/788, PCT/IN/12/000788, PCT/IN/12/00788, PCT/IN/2012/000788, PCT/IN/2012/00788, PCT/IN12/000788, PCT/IN12/00788, PCT/IN12000788, PCT/IN1200788, PCT/IN2012/000788, PCT/IN2012/00788, PCT/IN2012000788, PCT/IN201200788, WO 2014/087414 A1, WO 2014087414 A1, WO 2014087414A1, WO-A1-2014087414, WO2014/087414A1, WO2014087414 A1, WO2014087414A1|
|Inventores||Menon Krishnaprasad Chennazhi Sreerekha Pr. Chandini C. Mohan. V Nair Deepthy Deepthy|
|Solicitante||Amrita Vishwa Vidya Peetham University|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (19), Otras citas (1), Clasificaciones (6), Eventos legales (3)|
|Enlaces externos: Patentscope, Espacenet|
THE PATENTS ACT,1970
(39 of 1970) AND
THE PATENT RULES 2003
(See Sections 10 rule 13)
METALLIC TITANIUM -BASED CARDIOVASCULAR STENT WITH NANO - STRUCTURED SURFACE AND METHOD OF MANUFACTURING THEREOF
(a) Name : AMRITA VISHWAVIDYAPEETHAM represented by its Director, Amrita Centre of Nano Sciences, Dr. Shantikumar V. Nair
(b) Nationality : Indian.
(c) Address : "Elamakkara P.O., Cochin 682 041, Kerala
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention le Invention relates to the Art, Method and Manner of Titanium based cardiov ascufar Stents vith nanostructured surfaces.
FIELD OF THE INVENTION
A method of preparing biocompatible metallic stents based on titanium having a
nanostructured titania layer that promotes superior endothelialization, wit
simultaneous inhibition of smooth muscle cell proliferation and platelet adhesio
for specific use in cardiovascular applications is described. The method of
nanotexturing of stents involves subjecting the metallic surface to hydrothermal
treatment in alkaline conditions at elevated temperatures. This invention describes a medical device, which may be used for example, as a vascular (stent, heart valves), endotracheal or prostatic device.] BACKGROUND OF THE INVENTION
Cardiovascular diseases, including artherosclerosis, results from arterial narrowing due to the accumulation of fatty deposits on the arterial wall, which restricts blood flow through the vessel. Percutaneous transluminal angioplasty, referred to commonly as angioplasty, helps to enlarge the lumen of the affected artery by radial hydraulic expansion. However, in some instances, the vessel restenoses chronically or closes down acutely, negating the positive effects of angioplasty procedure . In the kind of vascular injury induced by artherosclerosis, vascular smooth muscle cells in the artery wall undergo hyperproliferation and invade and spread into the inner vessel lining, making the vessels susceptible to complete blockage when a local blood clotting occurs, leading to the death of tissues. Under such cases of severe artherosclerosis, medical devices or endoprostheses, commonly referred to as "stents" are proposed for mechanically keeping the vessel open, after completion of the angioplasty procedure , Stents are elongated tubular metallic structures, with either solid or lattice-like walls, and can either be balloon expandable or self-expanding. With the stent in place, restenosis may or may not be inhibited, but the degree of blockage would be reduced due to the structural strength of the stent opposing the inward force of any restenosis, thus maintaining the patency of the vessel. Such an endoluminal prosthesis device ultimately helps to repair, replace or correct a damaged blood vessel. The prosthesis can help rectify a variety of defects including stenosis of the vessel, thrombosis, occlusion or an aneurysm.
The stents deployed in conditions of artherosclerosis or other diseased states demands that the stent material be appropriately biocompatible, hemocompatible as well as mechanically durable. This necessitates the use of metals including titanium (Ti), 316L stainless steel (SS - medical grade), Nitinol (an alloy of Nickel and Titanium) and Cobalt-Chromium (CoCr), for vascular stenting applications . The stent material can induce allergic reactions in a significant percentage of patient population, as in the most commonly used Nickel containing materials such as Nitinol and even medical grade 3 6L SS, which contains nearly 12% Nickel. Titanium and its alloys are well known for its biocompatibility, corrosion resistance, toughness, durability, etc., making it an ideal material for vascular stents. However, in-stent restenosis is a known problem associated with using bare metal stents, eventually leading to thrombosis. This occurs due to excessive vascular smooth muscle cell (VSMC) proliferation as a result of injury at the time of stent implantation and dysfunction of endothelial cells (ECs).
Currently, these issues are largely addressed with the use of drug-eluting stents (DES) which relies on the release of anti cell-proliferative, immunosuppressive or anti-thrombotic drugs, that inhibits the proliferation of smooth muscle cells as well as reduce thrombus formation within the lumen. However, this strategy of drug-induced inhibition of hyperplasia also inhibits re- establishment of healthy endothelium, which can potentially enhance the chances of 'late stent thrombosis'. Thus, most of the patients are forced to survive on treatments such as anti-platelet therapy to reduce the risk of thrombosis at a later stage. Although drug-eluting stents appear to be a significant step forward in the treatment of coronary artery disease, there is concern regarding the long terms risk of sub-acute thrombosis associated with drug eluting stents . Moreover, drug coated stents are considerably more expensive than uncoated stents, and may be unnecessary for a relatively large percentage of angioplasty patients in which they are implanted, being prescribed mainly in cases to avoid quick, undesirable and adverse reactions soon after implantation. Recent studies revealed that for patients in which a drug-ccated stent was implanted after stenosis of a coronary vessel, the mortality rate is higher than for patients who were treated with an uncoated metal stent. The probability of death by cardiac infarction in the period of between 6 months and 3 years after the stent implantation was 32% higher in the DES treated patient group than the bare metallic stent patient group . The object of the present invention is to provide a stent, with which the risk of restenosis is reduced without having to use antiproliferative active substances. In this regard, a feasible approach to improving the above mentioned pitfalls of metallic stents is to provide a biocompatible metal surface that specifically promotes rapid endothelialization and blood compatibility, and simultaneously inhibit high smooth muscle cell proliferation. Such a biocompatible surface would also help to minimize or avoid any adverse foreign body responses. This can be achieved by providing appropriate surface treatments to the metallic stent surface, such as surface coatings and/or surface modifications . These can be accomplished by (i) providing coatings of polymers or nanocrystalline powders of ceramics such as hydoxyapatite, titanium dioxide, iridium oxide and titanium nitride, by plasma/thermal sprays or coating of noble metal oxides [US 567,815, US 6099561, US 6478815] [7-9] or coating with biornolecules (eg: proteins, heparin, RGD peptides) [US5660873, US20020087123, US20070037739] [10-12]; and (ii) creating nanoscale surface topography on substrates by fabrication techniques such as lithography, anodization, electrospinning, chemical treatment, hydrothermal treatment, electropolishing and sandblasting [US4988575, US200802171 6, US20090017636, US20100311576, US20060155361] [13-17]. The nanoscale topographies thus created on metallic surfaces have been established to significantly alter the cellular adhesion, proliferation, differentiation and gene expression and thereby influence the overall cellular behaviour [18, 19].
The surfaces with tunable nanoscale surface features can also exhibit varied wetting characteristics (such as hydrophilicity), which in turn affect the cellular interaction with the biomaterial as well as its blood compatibility. A desirable cellular response on nanostructured surfaces can lead to stronger biointegration with adjacent tissues, thereby increasing both lifetime and bonding between appropriate tissues and implant surfaces. A nanostructured stent surface can attach endothelial cells more easily than a smooth one, resulting in an accelerated endothelialisation process. The so formed endothelial layer is very smooth, thereby largely preventing thrombus formation and restenosis. However, more importandy, the endothelium forming over the stent should maintain its native functionality, capable of releasing antithrombogenic factors as well as factors inhibiting smooth muscle proliferation. Also, any surface coating or treatment provided should be completely adherent to the metal surface.
US Patent No: 2008/0147167A1 describes a method for producing a stent coated with a layer of noble metal oxide over the substrate composed of a less noble metal, to improve the biocompatibility and antiproliferative characteristics . However, there could be issues encountered in the stability of adhesion between the noble metal oxide layer such as iridium oxide and the less noble alloy or metal such as titanium or niobium or platinum enriched medical grade stainless steel.
US20090118813 disclosure relates to patterned endoprostheses that can facilitate selective endothelialization of the endoprosthesis surface . The endoprosthesis can have a patterned coating, wliich can be formed of materials such as titanium oxide, titanium nitride or iridium oxide. The patterned coating is suggested to aid in enhanced endothelialization and decreased adhesion and proliferation of smooth muscle cells, which can thereby reduce restenosis.
PCT Publication No. WO 99/07308 discloses stents wherein a portion of. a stent supporting structure is encapsulated with a thin flexible coating made of a polymer which can be used as a carrier for supporting therapeutic agents and drugs. When bioerodable polymers are used as drug delivery coatings, porosity is variously claimed to aid tissue ingrowth, make the erosion of the polymer more predictable, or regulate/ enhance the rate of drug release, as, for example, disclosed in U.S. Pat. Nos. 2010031232, 7901451 [22,23]. The non-encapsulated portions of the stents form porous exteriors rendering them more biocompatible while reducing blood clots. But the said stents have the disadvantage that they are complicated to manufacture and expensive. The above mentioned products have the drawback that the implant surfaces are provided with various kinds of coatings which can ultimately cause structural instabilities upon implantation and also is produced through stringent routes. The present invention focuses on producing a stable bioactive patterned stent surface that is easy to manufacture and economically viable, particularly favoring the endothelialization process with reduced smooth muscle proliferation and platelet adhesion. Recently, some of the authors of this invention published a simple, scalable as well as economic hydrothermal technique to generate various nanostructures under different alkaline conditions (NaOH) for preparing biocompatible orthopedic/dental implants [24,25].
The present invention utilizes this novel, versatile technique to produce an endovascular metallic device (stent) that aims at rectifying the causes responsible for restenosis after stent implantation, without the incorporation of any antiproliferative pharmaceutical agents. It follows that for successful interventional use, the stent should possess characteristics of relatively non-allergenic reaction, resistance to vessel recoil, sufficient thinness to rriinimize obstruction to flow of blood and biocompatibility to vessel, which can all be met through the use of nanostructured stents.
SUMMARY OF THE INVENTION
In the present invention, we disclose a product for vascular st nt applications (for eg. cardiovascular, neurovascular peripheral vascular stents) based on metallic titanium possessing uniform nanostructural surface topography of distinct morphology. The product based on surface modified titanium has been tested in vitro to demonstrate good endothelialization, with reduced smooth muscle cell proliferation, excellent blood compatibility and minimal platelet adhesion.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1. Schematic representation of the Ti endovascular prosthesis (stent in this case) (A) Outer diameter (B) inner diameter (C) Hole horizontal length (D) Hole Vertical width and (E) Strut width.
Fig. 2. Representative scanning electron micrograph images of the nanostructures generated on the stent implant by hydrothermal modification shown at different magnifications in (i), (ii) and (iii). (A) Ti implant surface before hydrothermal treatment; and hydrothermally modified Ti implants with nanostructural features (B) Structure A (C) Structure B; and (D) Structure C and (E) Control polished Ti
Fig. 3. Contact angle measured on nanostructured Ti surface (A) Structure A (B) Structure B (C) Structure C in comparison to (D) control surface.
Table 1. Surface energy values calculated for various nanomodified Ti surfaces from the contact angle values using the formula Es = Εύ, cosd
Fig. 4. Graph showing cell viability analysis using Alamar blue assay on various surfaces at 24, 72 and 120 h, with control polished surface as control (A) Enhanced cell viability of HUVECs (B) Decreased viability of SMC; Statistical significance was assessed relative to control nanopolished Ti for each nanostructure with * and ** denoting p<0.05, and p<0.01 versus control respectively.
Fig.5 Scanning electron micrographs and Actin fluorescent staining of HUVECs proliferation at two different incubation periods on various Ti surfaces - Structure A, Structure B, Structure C and control have been labeled as A, B, C and D respectively. (Ai to Di) SEM morphology analysis at 24 h (Aii to Dii) Fluorescent analysis at 24 h (Aiii to Diii) SEM morphology analysis at 72 h and (Aiv to Div) Fluorescent analysis at 72 h. Arrows indicates the philopodial extensions of cell proliferation on the nanosurfaces.
Fig. 6 Scanning electron micrographs and Actin fluorescent staining of SMCs proliferating on various surfaces - Structure A, Structure B, Structure C and control have been represented as A, B, C and D respectively. (Ai,ii to Di,ii) SEM morphology analysis at 72 h and (Αϋΐ,ίν to Diii,iv) Fluorescent analysis at 72 h. Higher magnification SEM micrographs are shown in inset on the right side. Arrows shown in the figure indicate the rounded SMCs as a result of nanomodification; Magnification: 60X
Fig. 7. Estimation of Nitric oxide release by HUVECs grown on modified Ti samples compared to control polished sample; n = 3; *p <0.05 in comparison with the control (B) LDL uptake by the HUVEC cultured on (Bi) Structure A (Bii) Structure B (Biii) Structure C and (Biv) control shows that cells are functionally active.
Fig. 8 Functionality analysis of SMC cultured on various Ti samples using Smooth muscle calponin and smooth muscle a-actin staining at 48 h (A) Structure A (B) Structure B (C) Structure C (D) Control using confocal microscopy. Red-calponin; Green-Smooth muscle actin. Right panel shows the merged images of SMA and Calponin; Magnification: 63X.
Fig. 9. Blood compatibility studies on various Ti surfaces using (A) Hemolysis assay (B) SEM image of platelet adhesion [i- Structure A, ii- Structure B, ii- Structure C, iv- Structure D, v- Positive control (lower magnification), vi- Positive control (higher magnification)] (C) Platelet aggregation by cell counter and D) Platelet activation by flow cytometry. DEFINITIONS:
As used herein, any component that is intended for long or short-term contact with biological tissues and also which does not induce any adverse biological response of the tissue is encompassed by the term "biocompatible component" or "biocompatibility" of the material. Example of such a biocompatible component is an implant such as cardiovascular, orthopaedic, or dental implants.
As used herein, the term "implant" includes within its scope any device that is intended to be implanted into a human body and that can serve the purpose of replacing the anatomy and/ or restoring any normal function of the body.
As used herein, the term "endovascular prostheses" can be a medical device that is tubular (e.g., a stent) and/or balloon extendable. As used herein, the term "endoprosthesis" refers to stent prototypes created through laser cutting. The term "nanosurface modification" refers to the process of surface modification wherein the metallic surface is treated chemically by one or many means to achieve a homogeneous / uniform surface topography with structural features in the nanoscale with dimensions ranging from 1 - 500 nm.
As used herein, the term "hydrothermal treatment" refers to a chemical technique of surface modification of the metal, wherein the metals are treated in a sealed autoclave at elevated temperature and pressure, in a chemical environment offered by alkaline solution and in certain cases a combination with suitable chelating agent, thereby providing a roughened nanotexture to the implant surface.
As used herein, the term "endothelialization" refers to the capability of implanted endovascular prosthesis to promote adhesion and proliferation of endothelial cells to cover the embodiment. 'inhibiting restenosis" means reducing the extent of restenosis observed following a vascular injury at the time of stent deployment, which is measured by average percentage reduction in the stenosis rate at a selected time following stent placement, e.g., 1-6 months.
As used herein, the term "blood compatibility" refers to the ability of the vascular implant in direct contact with blood to inhibit blood hemolysis; platelet adhesion, aggregation and activation; inhibit blood coagulation and clotting; provide minimal immunogenecity.
DETAILED DESCRIPTION OF THE INVENTION:
It is to be understood that schematic illustrations are not intended to be a representation to the scale of the. respective embodiment.
The present invention is focussed on development of a medical device for treating abnormalities of the cardiovascular system. Those with ordinary skill in the art will appreciate that the below described invention can be applied to other implantable medical devices.
The present invention relates to the development of implantable medical devices, which can be endovascular prosthesis (stents) based on nanosurface modified metals or metal alloys of titanium. For fabricating a titanium stent prototype, the presently preferred process is performed through the following sequence of steps: (i) tube processing from ingot (ii) laser cutting of tube (iii) mechanical and chemical finishing (iv) electropolishing (v) vacuum annealing; and (vi) hydrothermal processing in alkaline conditions for nanosl_ractaring.
It is the primary objective of the present invention to produce a biocompatible endovascular prosthesis based on metallic titanium having nanoscale roughness which is substantially uniform over the entire area of the implant that is intended to bond to the arterial tissue in a much improved fashion compared to existing implants where the surfaces are not modified.
Fig 1. is a perspective view of the endoprosthesis (stent) of an expanded hollow tubular self-supporting structure. In its expanded state, the embodiment has got an outer diameter of about 3-4 mm and a total length of 10-20 mm. In the laser cutting process, the tubular stent is provided with an array of through-holes or openings through sidewall, defined and bounded by struts or links that enables stent expansion at the target site. A conventional laser with narrow beam enables the precise cutting or opening to form a latticework sidewall following a programmable pattern. Lattice sidewall has a pattern of interconnected struts by creating a series of longitudinally repeating diamond shaped openings parallel to the longitudinal axis.
To prepare the endoprosthesis as in the present invention, mechanical and chemical finishing followed by electropolishing and vacuum annealing were carried out before the prosthesis was subjected to nanosurface modification by a hydrothermal processing technique in alkaline conditions. Surface modification of metal implants, particularly titanium and its alloys, results in a modified metallic oxide layer as detailed below.
The steps used to create the new endoprosthesis implant are listed. Similar procedures or procedures with appropriate modifications may be adopted to prepare nanosurface modified implants to suit different applications as in orthopaedic, dental, vascular, urethral, etc. For an implant surface that is already prepared to have a uniform surface finish after mechanical and chemical finishing followed by electropolishing and vacuum annealing, the following steps can be adopted to create nanoscale topography using hydrothermal processing. Step 1 - Surface cleaning of the mechanically coarsened, chemically finished, vacuum annealed Ti implant surface through successive ultrasonication in acetone and distilled water.
Step 2 - Treatment of the cleaned Ti implant in alkaline medium in an autoclave kept inside a high temperature furnace with programmable temperature controller to vary the temperature in the range of 100-300° C for different time intervals (1-10 hrs).
Step 3 - Drying of the hydrothermally treated Ti implant samples in a medically sterile environment and sterile sealing to obtain the finished product.
Fig. 2 gives electron micrographs of the varying surface features of Ti stent prototype. The above said processes fabricated on the metallic stent prototype (Fig. 2A) resulted in nanostructures with variable morphology, labelled as (B) Structure A (C) Structure B and (D) Structure C. These nanostructures are compared with conventional polished surfaces labelled as (Έ) Control.
Structure A obtained through hydrothermal processing of the stent has a foliate or leaf like 2D construct, formed of more or less flat, broad nanocues of width in the range of 135±43.3 nm and crevices in between, of dimensions 117±21.5 nm. Structure B discloses an architecture where, the Titania nanostructures form relatively organised pores with diameter varying as 109±42.2 nm. Pores are well defined by an outer wall separating each pore with thickness of approximately 55.8±10.5 nm. Structure C shows nanofeatures presenting a 1-D, more or less vertically aligned rod like morphology, with diameters of 114± 10.2 nm, with distance between the two features in the range of 146±71.3 nm. Again referring to Fig. 2, in some embodiments of the prosthesis, the features are distributed uniformly as an array of nanostructures over the surface. The features can vary to include rods, needles, pits, pores, mesh, spheres, and/or polygonal shapes such as triangles, squares, rectangles, diamonds, and hexagons depending on the processing conditions. An endovascular prosthesis of any desired shapes and sizes (for example, Ti or other metallic stents with prosthesis si2es ranging from 1 mm to 46 mm) can be processed to achieve the nanosurface features. In some embodiments, the features can be ordered or non-ordered, clustered or non-clustered, in phase or out-of-phase, parallel or non-parallel. In the present invention, a specific set of nanostructures have been selected for the in vitro analysis.
The in vitro efficacy of the implant has been established in the present invention through two approaches:
(i) In vitro evaluation of human umbilical vein endothelial cell (HUVEC) proliferation and inhibition of vascular smooth muscle cell proliferation (VSMCs) of nanosurface modified stents in comparison to control polished surface.
(ii) Hemocompatibility studies on nanosurface modified and unmodified Ti stent.
The surface modifications or topographies created on a particular substrate of the embodiment can be sensed by the cells as they adhere. Many factors, such as differences in surface energy gradients, hydrophobicity, hydrophilicity, charge, and/ or pH is supposed to affect cell adhesion and these properties are affected by topological and/ or chemical surface patterns. In some embodiments, surface modification can result in space confinements affecting the local solute concentration, cell wettability and protein exchange. Some embodiments show superior cellular adhesion and function on hydrophilic surfaces because of enhanced competitive binding and bioactivity of adhesion proteins such as fibronectin on hydrophilic surfaces, and/or an increased cellular ability to modify their interfacial proteins. The degree of hy<drophilicity/phobicity was estimated through contact angle measurements. Various nanoscale features on Ti showed altered water contact angles mdicating variations in their hydrophilicity, mainly due to the changes in surface area. For example, as seen from Fig 3, amongst the various nanostructures studied, Structure C was found to be highly hydrophilic, with a contact angle of less than 20°. Structures A and B showed moderate hydrophilicity with Θ = 34.4°± 4.48 & 44.5°± 3.16 respectively, when compared to the polished surface with Θ = 74.2°± 5.61. Thus, these variations in surface area are clearly reflected in the surface energy of the Ti samples calculated using the formula Es = Elv cos6 and shown in table 1.
A distinct feature of the present invention relates to the observation that nanosurface modification, of the kind produced by the hydrothermal process described, provided substantially improved in vitro biocompatibility, with enhanced endothelialisation and improved cellular functions, decreased adhesion of other cells such as smooth muscle cells, platelets, and/or monocytes in comparison to unmodified metallic surfaces. Cell proliferation studies revealed that all the developed nanostructure modified surfaces showed significantly enhanced cellular adhesion and proliferation than polished Ti after 1, 3 and 5 days of in-vitro culture using alamar blue assay (Fig 4). Enhanced proliferation was observed on Structure A in comparison to control-polished titanium and odier nanostructured implants. In embodiments with nanosttucturing, VSMC viability was badly affected, showing a significandy reduced VSMC proliferation with respect to the control polished surface.
Referring to Fig 8., an embodiment with nanosurface modification can influence the expression of SMC differentiation markers that helps to maintain the differentiated state of VSMCs, promoting a non-proliferative contractile phenotype. Staining of VSMCs on various modified and unmodified surfaces using intracellular SMC specific markers such as smooth muscle -actin (SMaA) and calponin suggest their efficacy as successful endovascular prosthesis (for eg. stents).
THE PRESENT INVENTION REFERS TO MEDICAL IMPLANTABLE DEVICES DEPLOY ABLE INSIDE A VESSEL WITHIN THE BODY OF A MAMMAL PATIENT. THE SUBSTRATE SURFACE CAN BE A SURFACE SELECTED FROM A GROUP OF ENDOVASCULAR PROSTHESIS INCLUDING VASCULAR STENTS (E.G., CORONARY STENTS, AORTIC STENTS, PERIPHERAL VASCULAR STENTS, NEUROVASCULAR STENTS), PROSTHESES FOR AORTIC ANEURYSMS AND VENA CAVA FILTERS AND HEART VALVES. SUCH IMPLANT SURFACES SHOULD PREVENT BLOOD CLOTTING AND INHIBIT IMMUNE RESPONSE UPON IMPLANTATION. REFERRING TO FIG 9, IN A PREFERRED EMBODIMENT OF THE PRESENT INVENTION, AN ENDOPROSTHESIS SURFACE HAVING NANOSTRUCTURAL MODIFICATIONS SHOWED ENHANCED BLOOD COMPATIBILITY, WITH DECREASED PROBABILITY OF THROMBOSIS TO OCCUR, AS COMPARED TO UNMODIFIED TI SURFACES, WITHOUT THE INCORPORATION OF ANY ANTLTHROMBOGENIC AGENTS. FOR EXAMPLE, MOLECULES SUCH AS HEPARIN ARE COMMONLY USED TO EXERT A POWERFUL ANIICOAGULANT EFFECT BY INDUCING THE INHIBITORY ACTION OF ANTITHR OMBIN III. IN THE PRESENT EMBODIMENT, ALL THE NANOSTRUCTURED SURFACES SHOWED REDUCED PLATELET ΑΟΤΓ/ΑΉΟΝ, PLATELET ADHESION, INFLAMMATORY RESPONSE AND HEMOLYSIS ON DIRECT CONTACT WITH BLOOD IN-VITRO, IN COMPARISON TO A POLISHED TI SURFACE
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|Clasificación internacional||A61L31/14, A61L31/02|
|Clasificación cooperativa||A61L31/022, A61L2400/18, A61L2400/12, A61L31/14|
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