Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2001-06-25
2002-11-26
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S081000, C554S082000, C556S024000, C556S113000
Reexamination Certificate
active
06486334
ABSTRACT:
CROSS REFERENCES TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with United States government support awarded by the following agencies: NSF DMR-9711226. The United States has certain rights in this invention.
BACKGROUND OF THE INVENTION
The present invention relates to artificial biocompatible surfaces. More particularly it relates to surfaces which mimic monolayer phospholipid structures in humans.
A wide variety of medical devices have been developed for insertion into the human body to form part of the human blood circulation system (e.g. vascular grafts; heart valves), and/or to be positioned at locations exposed to human blood (conduits in heart lung machines). However, clots, clogs and other problems can develop if such surfaces are not specially designed to minimize such problems (e.g. by making them biomimetic). In some applications this can even lead to increased risk of stroke.
Biomimetic surfaces are also of interest in connection with protein chromatography, biological sample support, enzyme immobilization, and DNA surface computing. They are also of interest for researching biological mechanisms.
Some artificial conduits have been produced that have surfaces that are formed by taking mold impressions from naturally occurring surface via microcasting. See e.g. U.S. Pat. No. 5,380,589. The disclosure of this patent, and of all other publications referred to herein, are incorporated by reference as if fully set forth herein. However, this molding technique is somewhat costly, and is not suitable for certain applications.
It has also been proposed to graft biocompatible polymer chains onto a substrate using a silicon linkage to form a biocompatible surface. See Z. Yang et al., 15 Langmuir 8405-8411 (1999) and Z. Yang et al., 9 Adv. Mater. 426-429 (1997). However, this approach is unlikely to be useful in certain in vivo applications requiring long-term stability and durability.
There has also been some discussion of covalently linking phospholipids on a silicate gel surface for chromatography applications. See C. Pidgeon et al., 176 Anal. Biochem. 36 (1989).
In Z. Yang et al., 15 Langmuir 1731-1737 (1999) it was proposed to form biomembrane mimetic surfaces by phospholipid self-assembled monolayers. However, the linkage we proposed relied on silicon. This rendered the structure unsuitable for certain in vivo applications.
There has also been discussion of the use of thiol linkages between some compounds and fixed surfaces. See e.g. R. Nuzzo et al., 105 J. Am. Chem. Soc. 4481 (1983); T. Li et al., 106 J. Am. Chem. Soc. 6107 (1984); and K. Prime et al., 252 Science 1164 (1991). However in each case the compounds did not sufficiently address biomimetic needs.
Thus, a need exists for biomimetic surfaces which are compatible with the human body, stable long-term, and durable.
BRIEF SUMMARY OF THE INVENTION
One aspect the invention provides a compound having the following moiety:
wherein R
1
, R
2
and R
3
are individually selected from the group consisting of CH
3
and H, n is 10 to 24, R
4
is alkyl with less than six carbons, n′ is 10 to 24, and M is selected from the group consisting of Au, Ag and mixtures thereof. In a preferred form both n and n′ are 12, M is Au, each of R
1
, R
2
and R
3
are CH
3
, and R
4
is CH
2
CH
2
.
In another aspect, the invention provides a method of forming such compounds. One reacts a compound having the following moiety:
with H
2
N—R
4
—SH, and then covalently links the resultant to M. R
1
, R
2
and R
3
are individually selected from the group consisting of CH
3
and H, R
4
is alkyl with less than six carbons, n is 10 to 24, n′ is 10 to 24, and M is selected from the group consisting of Au, Ag and mixtures thereof.
Still another aspect the invention provides a compound having the following formula:
wherein R
1
, R
2
and R
3
are individually selected from the group consisting of CH
3
and H, R
4
is alkyl with less than six carbons, n is 10 to 24, and n′ is 10 to 24. In a preferred form both n and n′ are 12, each of R
1
, R
2
and R
3
are CH
3
, and R
4
is CH
2
CH
2
.
There is a naturally occurring phospholipid in many blood-containing conduits. We have developed a way to stably link this type of phospholipid to a durable substrate (e.g. gold coated glass). The resulting array presents a well ordered monolayer of exposed phospholipid that closely mimics a layer of the naturally occurring material.
Advantages of the present invention are to provide biomimetic surfaces that can be efficiently produced and which appear to be highly compatible with the human body. Further, such structures appear to be highly durable and stable. It is also an advantage to provide efficient methods for forming such compounds and structures, and intermediates useful for such purposes.
These and other advantages of the present invention will become apparent after study of the following specification and claims.
REFERENCES:
patent: 5380589 (1995-01-01), Goodman et al.
patent: 5801260 (1998-09-01), Yu et al.
Z. Yang et al., Protein Interactions With Poly(ethylene glycol) Self-Assembled Monolayers On Glass Substrates, Diffusion And Adsorption; 15 Langmuir 8405-8411 (1999).
Z. Yang et al., Preserving A Globular Protein Shape On Glass Slides: A Self-Assembled Monolayer Approach, 9 Adv. Mater. 426-429 (1997).
Z. Yang et al., Biomembrane Mimetic Surfaces By Phospholipid Self-Assembled Monolayers On Silica Substrates, 15 Langmuir 1731-1737 (1999).
C. Pidgeon et al., Immobilized Artificial Membrane Chromatography: Supports Composed of Membrane Lipids, 176 Anal. Biochem. 36-47 (1989).
R. Nuzzo et al., 105 J. Am. Chem. Soc. Adsorption Of Bifunctional Organic Disulfides On Gold Surfaces, 4481-4483 (1983).
T. Li et al., Intramolecular Electron Transfer At Metal Surfaces . . . 106 J. Am. Chem. Soc. 6107-6108 (1984).
K. Prime et al., Self-Assembled Organic Monolayers: Model Systems For Studying Adsorption Of Proteins At Surfaces 252 Science 1164-1167 (1991).
D. Seebach et al., &bgr;-Peptides . . . 79 Helv. Chim. Acta 913-941 (1996).
M. Bodanszky et al., The Practice Of Peptide Synthesis, 119 Springer-Verlag, Berlin (1984).
Jiang Xiqun
Park Sang-wook
Strother Charles M.
Yu Hyuk
Nazario-Gonzalez Porfirio
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
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