Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Polymers from only ethylenic monomers or processes of...
Reexamination Certificate
2003-06-02
2004-03-02
Zalukaeva, Tatyana (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Polymers from only ethylenic monomers or processes of...
C526S285000, C526S310000, C424S450000, C427S407100, C428S035700, C428S402200
Reexamination Certificate
active
06699952
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to biocompatible materials. In particular, the present invention relates to cytomimetic systems having stabilized, phosphatidylcholine-containing polymeric surfaces. The biomaterials produced in accordance with the invention comprise various modular surface designs and have various applications such as in medical devices, vascular grafts, surgical equipment, drug delivery systems, etc.
BACKGROUND OF THE RELATED ART
The ability to repair, reconstruct and replace components of the human cardiovascular system is dependent upon the availability of blood compatible biomaterials. Biocompatibility refers to the interactions of living body tissues, compounds and fluids, including blood, etc., with any implanted or contacting polymeric material (biomaterial). Biocompatible biomaterials are of great importance in any biomedical application including, for example, in the implantation of vascular grafts and medical devices such as artificial organs, artificial heart valves, artificial joints, synthetic and intraocular lenses, electrodes, catheters and various other prosthetic devices into or on the body. Such applications, however, have been hampered by the lack of suitable synthetic materials that are stable when contacted with physiological fluids, particularly blood.
Exposure of synthetic biomaterials to body fluids such as blood, for example, can result in adverse reactions such as the formation of thrombi due to deposition of blood proteins (e.g., albumin, immunoglobulins, etc.) and/or adsorption of cell adhesive proteins (e.g., fibrinogen, fibronectin, vitronectin, etc.) causing platelet adhesion, activation and aggregation, as well as activation of the clotting cascade. Additionally, immune complexes can develop and stimulate undesirable immune responses such as proteolysis, cell lysis, opsonization, anaphylaxis, chemotaxis, etc.
Several approaches have been proposed for improving the biocompatibility of biomaterials useful in medical applications. For example, modifying the biomaterial surface to provide either low polarity or ionic charge or coating the surface with biological substances such as cells, proteins, enzymes, etc. has been used to prevent undesirable protein adhesion. Another approach involves the incorporation of an anticoagulant into the biomaterial, rendering the biomaterial antithrombogenic. A further approach involves the incorporation of various phospholipids into the biomaterial. An additional approach involves the binding of a heparin-quaternary amine complex, or other antithrombotic agent, to the biomaterial surface. However, many of these methods have the disadvantage of being nonpermanent systems in that the surface coating is eventually stripped off or leached away. For example, heparin, which is complexed to the biomaterial surface, is not only gradually lost from the polymer surface into the surrounding medium but also has limited bioactivity due to catabolism and its inherent instability under physiological conditions.
Thus, a need still exists for a biocompatible material for use in various medical applications possessing desired physical and surface characteristics and also exhibiting antithrombogenic properties.
One of the most intriguing developments in the past decade has been the recognition that membrane-mimetic systems having a phosphorylcholine component limit the induction of surface-associated blood clot formation. This biological property has been attributed to the large amount of surface bound water due to the zwitterion structure of the phosphorylcholine head group. It has also been suggested that specific plasma proteins which inhibit the blood clotting process are selectively adsorbed to this head group (Chapman [1993
] Langmuir
9:39).
Natural membranes are utilized as models for the molecular engineering of membrane-mimetic biosystems because of the potential biological activities associated with natural membranes and their ability to self-organize as non-covalent aggregates. Phospholipids differing in chemical composition, saturation, and size have been utilized as building blocks in the design of structures of complex geometry, including lipid-based cylinders, cubes, and spheres. Surface-coupled bilayers have been produced by assembling a layer of closely packed hydrocarbon chains followed by exposure to either a dilute solution of emulsified lipids or unilamellar lipid vesicles (Spinke et al. [1992
] Biophys. J.
63:1667; Florin et al. [1993
] Biophys J.
64:375; Seifert et al. [1993
] Biophys. J.
64:384). Langmuir-Blodgett techniques have also been used to construct supported bilayers via a process of controlled dipping of a substrate through an organic amphiphilic monolayer (Ulman [1991
] An Introduction to Ultrathin Organic Films from Langmuir
-
Blodgett to Self
-
Assembly,
New York: Academic Press). The overall significance of these design strategies lies in the ability to engineer surfaces in which the constituent members can be controlled, modified, and easily assembled with a high level of control over both order and chemistry. Of particular importance is the dialkyl moiety which facilitates the assembly of lipids with dissimilar head groups into surface structures of diverse biomolecular functionality and activity. Nonetheless, limited stability remains the major practical limitation of substrate supported membranes in which the constituent members are associated solely by non-covalent interactions.
In order to create robust surface structures, most membrane-mimetic systems for blood-contacting applications have been designed as copolymers containing the phosphorylcholine functional group in either side chains or, less frequently, the polymer backbone (Kojima et al. [1991
] Biomaterials
12:121; Ueda, T. et al., [1992
] Polym. J
24:1259; Ishihara, K. et al. [1995
] Biomaterials
16:873; Campbell et al. [1994
] ASAIO J.
40(3):M853; Chen et al. [1996
] J. Appl. Polym. Sci.
60:455; and Yamada et al. [1995
] JMS Pure Appl. Chem.
A32:1723). While these materials have improved stability and promising blood-contacting properties have been reported, a number of limitations exist. In particular, the ability to engineer surface properties on a molecular level by taking advantage of the principle of self-organization intrinsic to amphiphilic molecules is lost. In addition, the ability to early incorporate diverse biomolecular functional groups into the membrane-mimetic surface is also lost.
The present invention provides the synthesis of stabilized, phosphorylcholine-containing polymeric surfaces by first attaching or incorporating a self-assembled acryloyloxy-containing phospholipid monolayer on an alkylated substrate and then subjecting the unit to in situ polymerization. This invention contemplates the production of the biomaterial through a process of assembly on a supported monolayer of modular surface design units, each possessing the desired physicochemical surface properties. Specifically, an example is provided of a generated surface which exhibits improved in vivo blood biocompatibility in a primate animal model.
The present invention also provides a new biomimetic approach for generating an ultra-thin organic barrier with the capacity for tailored transport and surface properties based upon a membrane-mimetic strategy. The extension of previous methodologies recently developed were utilized to produce a stable, lipid membrane-like bilayer on a hydrated alginate substrate. Marra, K. C. et al.,
Macromolecules
30:6483 (1997); Marra, K. C. et al.,
Langmuir
13:5697 (1997).
Transport characteristics and biocompatibility are critical membrane design properties for both the generation of controlled release drug delivery systems and capsules formulated as immunoisolation barriers for cell based therapy. Typically, membranes are produced with a variety of permeabilities by phase inversion processes whereby polymer precipitation time, polymer-diluent comp
Chaikof Elliot L.
Chon John H.
Marra Kacey G.
Emory University
Greenlee Winner and Sullivan P.C.
Zalukaeva Tatyana
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