Stock material or miscellaneous articles – All metal or with adjacent metals – Composite; i.e. – plural – adjacent – spatially distinct metal...
Reexamination Certificate
2000-09-22
2003-11-11
La Villa, Michael (Department: 1775)
Stock material or miscellaneous articles
All metal or with adjacent metals
Composite; i.e., plural, adjacent, spatially distinct metal...
C428S704000, C428S450000, C428S639000, C428S660000, C428S338000, C428S472300, C623S016110, C623S023760
Reexamination Certificate
active
06645644
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to organic phosphonate and inorganic phosphate coatings covalently bonded to substrates having hydroxide-bearing surface layers. The present invention further relates to implantable medical devices having hydroxide-bearing surface layers covalently bonded to the organic phosphonate and inorganic phosphate coatings, which provide an osteoconductive surface on the medical device. In addition, the present invention relates to methods for forming such coatings, particularly on the surface of implantable medical devices having hydroxide-bearing surface layers, to provide an osteoconductive surface.
BACKGROUND ART
Creating a stable bond between bone tissue and the surface of metallic bone implants is a research topic of considerable interest. Poor bonding with the interface between the metallic surface of the implant and the bone tissue leads to low mechanical strength of the bone-to-implant junction and the possibility of subsequent implant failure.
Titanium and titanium alloys are used extensively as dental and orthopedic implants. Currently, there is no effective way to obtain strong attachment of incipient bone with the implant material at the interface between the surfaces of the two materials in order to “stabilize” the implant.
An important goal for interface optimization is to use species which are biocompatible and which enable bone mineralization at the interface following implantation. Bone tissue is a combination of protein and mineral content, with the mineral content being in the form of hydroxyapatite.
The problem of interface synthesis is often approached from the prospective of high temperature methods, including using plasma or laser-induced coating techniques. However, these methods engender problems of implant heating and surface coverage. For example, calcium phosphate deposition at high temperatures can give rise to ion migration. Plasma-induced phosphate coating of a titanium substrate gives surface hydroxyapatite as well as surface calcium phosphate, titanates and zirconates. Therefore, control of surface stoichiometry can be problematic, and defects at the interface may translate into poor mechanical strength.
The use of intermediate layers, for example of zirconium dioxide, to enhance hydroxyapatite adhesion and interface mechanical strength has been explored with success. However, a practical limitation involving laser or plasma deposition is that it is hard to obtain comprehensive coverage on a titanium implant of complex 3-dimensional structure. The zirconium dioxide interface formed at high temperatures is of low surface area and maintains few, if any, reactive functional groups for further surface modification chemistry.
Solution-phase surface processing does not suffer from the practical limitations of surface coverage that can be attendant with plasma or laser-based deposition methods, and procedures involving formation of hydroxyapatite from solution, often using sol-gel type processing, have been accomplished. Elegant methodologies have been developed in which graded interfaces have been prepared, extending from the pure implant metal to the biomaterial at the outer extremity by way of silicates. However, while solution-based procedures are inexpensive and give rise to materials resistant to dissolution by bodily fluids, adhesion of the hydroxyapatite to the implant metal is less strong than is observed when deposition is accomplished by plasma spraying techniques.
A need exists for a methodology that combines the benefits of the physical deposition of interfacial zirconium dioxide with the coverage, processing and speciation control of solution-based methods.
SUMMARY OF THE INVENTION
This need is met by the present invention. It has now been found that alkoxides of transition metals selected from Group IVB, Group VB and Group VIB of the Periodic Chart adhere to hydroxide-bearing substrate surfaces with relative ease. Such transition metal alkoxides thus may be used to form osteoconductive interfaces between bone tissue and implant materials. In particular, the transition metal alkoxides covalently bond phosphates and phosphonates to the surface hydroxyls of the implant substrate, which in turn provide an osteoconductive surface imparting enhanced mechanical strength and stability to bone-to-metal implant interaction. The phosphate or phosphonate interface functions to nucleate the growth of hydroxyapatite, thereby minimizing implant failure and the attendant need for serial revision implant surgery, which can be a consequence of unstable implant-to-bone interaction.
Therefore, in accordance with one embodiment of the present invention, there is provided a surface layer on a hydroxide bearing substrate, wherein transition metal atoms selected from Group IVB, Group VB or Group VIB of the Periodic Chart are covalently bonded to the surface hydroxyls of the substrate, and each transition metal atom is further covalently bonded to one or more ligands, thereby covalently bonding the ligands to the substrate surface. Preferred ligands include phosphate ligand, organic ligands of carboxylic and phosphonic acids containing between 2 and 20 carbon atoms, and ligands of pi-electron delocalized compounds. The phosphonic acid ligand may be functionalized to promote bonding to the protein content of bone tissue. Preferred pi-electron delocalized compounds include aromatic ring compounds with the preferred ligand being a phenolate.
Hydroxide-bearing substrates suitable for use with the present invention includes substrates having a native oxide surface layer, including the native oxide layers of metals and metal alloys. Single or mixed metal oxides may also be used. Native oxide layers of metalloids such as silicon are also appropriate. Surface modified ceramics and polymeric plastics may also be used.
While not being bound by any particular theory, it is believed, under ambient conditions, that in the absence of a transition metal atom interface, the ligands adhere to substrate hydroxides by hydrogen bonding, which is a weak interaction. The introduction of a transition metal interface makes a significant difference in the stability of the ligand surface layer by covalently bonding the ligand to the substrate surface. In particular, phosphoric and phosphonic acids react instantaneously and irreversibly under ambient conditions with surface-bound transition metal alkoxides to provide strong adhesion of the organic ligand layer to the surface. No such adhesion exists in the absence of the transition metal interface under ambient reaction conditions.
The present invention also provides a method by which ligands may be covalently bonded to the surface of hydroxide-bearing substrates. In accordance with this embodiment of the present invention, there is provided a method of forming a ligand layer on the surface of a hydroxide bearing substrate, which method includes the steps of:
providing a hydroxide-bearing substrate having a surface layer of alkoxides of transition metals selected from Group IVB, Group VB or Group VIB of the Periodic Chart covalently bonded thereto, wherein the alkoxides are bonded at the transition metal atoms to the surface hydroxyls of the substrate overlayer; and
reacting the transition metal alkoxide surface layer with a compound capable of reacting with the transition metal alkoxide to form a ligand covalently bonded to the transition metal, thereby forming a ligand layer on the surface of the substrate, covalently bonded at the transition metal atoms to the surface hydroxyls of the substrate.
Phosphate ligands are obtained by using phosphoric acid. Phosphonate ligands are obtained using organic phosphonates.
The hydroxide-bearing substrate is preferably provided with a transition metal alkoxide surface layer by reacting the substrate with a polyalkoxide of the transition metal having two or more alkoxide groups, so that the transition metal alkoxide surface layer is formed, covalently bonded to at least one surface hydroxyl of the substrate, and having at least one unreacted alkoxide gr
Avaltroni Michael
Gawalt Ellen
Schwartz Jeffrey
La Villa Michael
Synnestvedt & Lechner LLP
The Trustees of Princeton University
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