Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1997-12-30
2002-04-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S423000, C424S426000, C424S428000, C424S433000, C530S350000, C530S353000
Reexamination Certificate
active
06372228
ABSTRACT:
TECHNICAL FIELD
The present invention relates to elastin and elastin-based biomaterials, to tropoelastin materials, particularly to methods of producing such materials, more particularly to methods of using same in tissue repair and replacement.
BACKGROUND OF THE INVENTION
Elastic fibers are responsible for the elastic properties of several tissues such as skin and lung, as well as arteries, and are composed of two morphologically distinct components, elastin and microfibrils. Microfibrils make up the quantitatively smaller component of the fibers and play an important role in elastic fiber structure and assembly.
The most abundant component of elastic fibers is elastin. The entropy of relaxation of elastin is responsible for the rubber-like elasticity of elastic fibers. Elastin is an extracellular matrix protein that is ubiquitous in mammals. Elastin is found, for example, in skin, blood vessels, and tissues of the lung where it imparts strength, elasticity and flexibility. In addition, elastin, which is prevalent in the internal elastic lamina (IEL) and external elastic lamina (EEL) of the normal artery, may inhibit the migration of smooth muscle cells into the intima. Elastin in the form of solubilized peptides has been shown to inhibit the migration of smooth muscle cells in response to platelet-derived factors (Ooyama et al, Arter-iosclerosis 7:593 (1987). Elastin repeat hexapeptides attract bovine aortic endothelial cells (Long et al, J. Cell. Physiol. 140:512 (1989) and elastin nonapeptides have been shown to attract fibroblasts (U.S. Pat. No. 4,976,734). The present invention takes advantage of these physical and biochemical properties of elastin.
Thirty to forty percent of atherosclerotic stenoses are opened with balloon angioplasty restenose as a result of ingrowth of medial cells. Smooth muscle ingrowth into the intima appears to be more prevalent in sections of the artery where the IEL of the artery is ripped, torn, or missing, as in severe dilatation injury from balloon angioplasty, vessel anastomoses, or other vessel trauma that results in tearing or removal of the elastic lamina. While repair of the arterial wall occurs following injury, the elastin structures IEL and EEL do not reorganize. Since these components play major structural and regulatory roles, their destruction is accompanied by muscle cell migration. There are also diseases that are associated with weakness in the vessel wall that result in aneurysms that can ultimately rupture, as well as other events that are, at least in part, related to abnormalities of elastin.
In vertebrates elastin is formed through the secretion and crosslinking of tropoelastin, the 72-kDa biosynthetic precursor to elastin. This is discussed, for example, in an article entitled “Oxidation, Cross-linking, and Insolubilization of Recombinant Crosslinked Tropoelastin by Purified Lysyl Oxidase” by Bedell-Hogan, et al in the Journal of Biological Chemistry, Vol. 268, No. 14, on pages 10345-10350 (1993).
In vascular replacement and repair, the best current option is to implant autologous veins and arteries where the obvious limit is the supply of vessels which can be sacrificed from the tissues they were intended to service. Autologous vein replacements for damaged arteries also tend to be only a temporary measure since they can deteriorate in a few years in high pressure arterial circulation.
When autologous graft material is not available, the surgeon must choose between sacrificing the vessel, and potentially the tissue it sub-served, or replacing the vessel with synthetic materials such as Dacron or Gore-tex. Intravascular compatibility indicate that several “biocompatible polymers”, including Dacron, invoke hyperplastic response, with inflammation particularly at the interface between native tissue and the synthetic implant. Incomplete healing is also due, in part, to a compliance mismatch between currently used synthetic biomaterials and native tissues.
As described in the prior co-pending patent applications set forth above (U.S. Ser. No. 08/341,881, filed Nov. 15, 1994, U.S. Pat. No. 5,989,244; U.S. Ser. No. 08/658,855, filed May 31, 1996, now U.S. Pat. No. 5,990,379; U.S. Ser. No. 08/797,770, filed Feb. 7, 1997, U.S. Ser. No. 08/798,425, filed Feb. 7, 1997, now U.S. Pat. No. 6,087,552; U.S. Ser. No. 08/798,426 filed Feb. 7, 1997, now U.S. Pat. No. 6,110,212) which are incorporated herein by reference, elastin and elastin-based biomaterials, or tropoelastin materials, can be used in a number of medical applications. For example, these materials can be employed to provide a method of effecting repair or replacement or supporting a section of a body tissue, as a stent, such as a vascular stent, or as conduit replacement, or as an artery, vein or a ureter replacement, or as a stent or conduit covering or coating or lining. It can also provide a graft suitable for use in repairing a lumen wall, or in tissue replacement or repair in, for example, interior bladder replacement or repair, intestine, tube replacement or repair such as fallopian tubes, esophagus such as for esophageal varicies, ureter, artery such as for aneurysm, vein, stomach, lung, heart such as congenital cardiac repair, or colon repair or replacement, or skin repair or replacement, or as a cosmetic implantation or breast implant.
SUMMARY OF THE INVENTION
A problem with using elastin or elastin-based materials or tropoelastin materials or tropoelastin materials in the aforementioned applications is that when are implanted in vivo, calcification thereof will occur. The effect of calcification of the implanted materials is that it prevents the effective and efficient operation of these material for the intended in vivo use. This can happen, for example, when one of the first and second outer surfaces of the elastin or elastin-based materials or tropoelastin material, and a tissue substrate, are fused together. The present invention also relates to a method of pretreating elastin and elastin-based materials or tropoelastin materials which can be employed in the repairing, replacing or supporting a section of a body tissue.
A method is therefore provided for producing elastin or elastin-based materials or tropoelastin materials which, on implantation, has a substantially reduced level of in vivo calcification as compared with elastin or elastin-based materials or tropoelastin materials produced from non-pretreated counterpart unreacted elastin or elastin-based biomaterials or tropoelastin materials. These materials are typically capable of being formed into a fused layer.
The subject method comprises providing unreacted elastin or elastin-based biomaterials or tropoelastin materials, and pretreating the unreacted materials with an aliphatic alcohol prior to reaction thereof. When the pretreated unreacted elastin or elastin-based biomaterials or tropoelastin materials are reacted subsequently, elastin or elastin-based materials or tropoelastin materials are implanted, they exhibit a substantially reduced level of in vivo calcification as compared to the level of vivo calcification for elastin or elastin-based materials or tropoelastin materials produced from non-pretreated counterpart unreacted elastin or elastin-based biomaterials or tropoelastin materials.
The aliphatic alcohol employed in present invention is typically a lower aliphatic alcohol, preferably a lower aliphatic alcohol comprises from one to eight carbon atoms, more preferably a lower aliphatic alcohol comprises from two to four carbon atoms, the most preferred lower aliphatic alcohol being ethanol.
The method of this invention can comprise positioning elastin and elastin-based materials or tropoelastin materials at the site of the section and bonding the biomaterial to the site or to the tissue surrounding the site. The bonding is effected by contacting the elastin material and the site, or tissue surrounding the site, at the point at which the bonding is to be effected, with an energy absorbing agent. The agent is then exposed to an amount of energy absorbable by the agent sufficient to bond the el
Channavajjala Lakshmi
Gregory Kenton W.
Marger & Johnson & McCollom, P.C.
Page Thurman K.
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