Coating processes – Medical or dental purpose product; parts; subcombinations;...
Reexamination Certificate
1993-05-18
2003-02-18
Yamnitzky, Marie (Department: 1774)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
C427S002280, C427S002300, C424S422000
Reexamination Certificate
active
06521283
ABSTRACT:
The present invention relates to the treatment of the surfaces of blood-contacting materials and devices to reduce the thrombogenicity of the materials.
Many modern surgical and other medical procedures, sampling techniques and test procedures involve the use of blood-contacting devices, such as catheters, drains and extracorporeal circuitry. These devices are used only once and then discarded for hygiene reasons and must therefore be constructed from the most economical materials available, usually polymeric plastics or glass. However glass and most synthetic and natural polymers tend to induce platelet aggregation and initiate the fibrinolytic clotting cascade leading to blockage of tubing and clogging of other apparatus such as filtration and dialysis membranes, interference with test procedures and, in certain cases, may have disastrous consequences for patients.
With existing technology, extra-corporeal circulation for haemodialysis, long term gas exchange at states of severe respiratory failure and cardiac support, e.g. after cardiac surgery, all require systemic heparinisation. Owing to the risk of excessive bleeding after systemic anticoagulant treatment many patients are disqualified for possible therapeutic measures. Likewise, commercial catheter sensors, e.g. for continuous determination of arterial oxygen, carbon dioxide tension, and of pH in the critically ill patient require systemic heparinisation to prevent microclotting on the sensor membranes and failure of the device.
It has been suggested that heparinisation of apparatus, particularly involving end point attachment of heparin fragments, will result in anti-thrombogenic coating of surfaces and thereby overcome the need for systemic heparinisation. Thus a method was developed in which heparin was coupled by end point attachment [Hoffman, J. et al.,
Carboyhdr, Res
., 117:328(1983), Larm, O. et al.,
Biomat. Med. Dev. Art. Org
., 11:161(1983)]. The resulting surfaces adsorbed antithrombin and large amounts of thrombin which were rapidly inhibited in the presence of antithrombin [Pasche, B, et al.,
Thromb. Res
., 44 739(1986)]. It is interesting to note that end-point attached heparin and the endothelium behave both quantitatively and qualitatively alike with respect to the inhibition of thrombin in the presence of plasma [Arnander C., et al.,
J. Biomed. Mat. Res
., 20:235(1986)] and that a polyethylene surface furnished with end-point attached heparin showed considerable capacity to inhibit Factor Xa [Kodama, K. et al.
Thromb. Haemostas
. (1987)].
Rigid polyethylene tubing sections with end-point attached heparin have been kept in the thoracic aorta of pigs for up to four months [Arnander C., et al.,
Biomat. Res
., (1987)]. When applied to vascular grafts of expanded polytetrafluoroethylene (PTFE) and to polyurethanes and implanted in the arteries of the sheep [Esquivel, C. O. et al.,
Surgery
, 95:102(1984)], the end-point attached heparin surface substantially reduced the platelet and fibrin deposition.
The extra-corporeal circulation of blood through surface-heparinised devices offered the possibility to discriminate between the role of platelets and the plasma coagulation system as the main determining factor for achieving thromboresistance. In these experiments, it was demonstrated that coatings with other sulfated polymers were as platelet compatible as the heparin coatings, but still thrombogenic. Using the radioimmunoassay for fibrinopeptide A [Nossel, H. L. et al.,
J. Clin. Invest
., 54:43(1974)] it was shown that only coatings on which the heparin molecules could interact with plasma constituents were able to prevent conversion of fibrinogen to fibrin on contact with blood [Larsson R. and Lindahl U.
Artif. Org
., Vol 3. Suppl. Proc. of the second meeting of the Intern. Soc. Artif. Org., (1979); Larsson R., et al.,
Thromb. Res
., 19:43(1980); Larm, O. et al.,
Biomat. Med. Dev. Art. org
., 11:161(1983)].
Thus the presence of intact functional groups on the immobilised heparin appeared mandatory for achieving thromboresistance and heparin coatings on blood-contacting medical devices could eliminate hazardous systemic anticoagulant treatment.
Experimental haemodialysis has been performed on dogs without systemic heparinisation and with cellulose acetate hollow fibers filters with end-point attached heparin surfaces. The efficiency of the coating on the total extra-corporeal system was demonstrated by the fact that the levels of fibrinopeptide A in the dialysed animals were not higher than in anaesthetised control animals with no surgery [Arnander C., et al.,
Proc. Eur. Soc. Art. Org
., 9:312(1982), Lins, L. E et al.,
Proc. EDTA-ERA
, 21:270(1984). When end-point attached heparin surfaces were used in the extra-corporeal circuit, veno-venous by-pass for carbon dioxide elimination was easily performed for 24 h on dogs in a steady-state condition. After a small release of heparin, the coagulation system seemed unaffected as determined by fibrinopeptide A levels in the circulating blood [Larm, O. et al., An approach to antithrombosis by surface modification. Progress in artificial organs, ISAIO Press, Cleveland 1986, p313. Inacio, J. et al., Extracorporeal elimination of carbon dioxide using a surface heparinised vein-to-vein bypass system. EUROXY Workshop on design and techniques of extracorporeal gas exchange. Paris, Jun. 20, 1985. Bindsley L., et al.,
Trans. Am. Soc. Art. Int. Org
. 32:530(1986).
Although heparinisation can reduce or prevent fibrinolytic clotting, this is at the expense of interference with the blood biochemistry, for instance the complexation of antithrombin and other subtle alterations. The heparinised surfaces are exerting many of the effects of heparin when administered as an anti-coagulant drug and the adverse side effects of heparin must, therefore, be taken into account when this technique is employed to improve haemocompatibility of blood-contacting devices.
Much effort has been devoted in recent years to the development of surface treatments, especially by covalent bonding of haemocompatible organic groups which improve the biocompatibility of blood-contacting surfaces and to the production of more biocompatible materials for use in blood-contacting devices such as surgical implants, prostheses and artificial hearts (see, for instance EP-A-0032 622 and EP-A-O 157 496). However, being intended to provide long term biocompatibility, these tend to be relatively expensive and are therefore less suitable for use in low-cost, single-use disposable devices.
The present invention provides a simple and cost effective means for reducing the thrombogenicity of blood-contacting surfaces using readily available materials.
The coatings of the present invention do not interfere with blood biochemistry in any manner and are therefore regarded as non-thrombogenic rather than as anti-thrombogenic. In addition to avoiding the side-effects of heparinisation, the present treatment offers the further advantages in many applications in that the coated surfaces have improved wetability and improved lubricity. This assists in, for instance, avoiding the formation of gas bubbles in tubing and facilitating insertion of catheters via surgical incisions.
According to the invention there is provided a process for coating a blood-contacting surface comprising applying a solution of a fatty acid diester of phosphatidyl choline in an organic solvent to the surface and removing the solvent.
FIG. 1
shows a comparison between a piece of medical tubing treated using the process of the invention and a similar tube of untreated medical tubing.
The surface to be treated may optionally be prepared for coating by washing to remove surface contaminants and, to improve the adhesion of the coating, by silylation or otherwise increasing the hydrophobicity of the surface.
The thickness of the coating will be selected according to the intended use of the blood-contacting device. Thus surfaces subjected to shear forces, such a
Biocompatibles Limited
Yamnitzky Marie
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