Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
2001-03-30
2003-01-21
Tate, Christopher R. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C424S423000
Reexamination Certificate
active
06509145
ABSTRACT:
BACKGROUND OF THE INVENTION
The surgical implantation of prosthetic devices (prostheses) into humans and other mammals has been carried out with increasing frequency. Such prostheses include, by way of illustration, heart valves, vascular grafts, urinary bladders, heart bladders, left ventricular-assist devices, and the like. The prostheses may be constructed from natural tissues, inorganic materials, synthetic polymers, or combinations thereof. By way of illustration, mechanical heart valve prostheses typically are composed of rigid materials, such as polymers, carbon-based materials, and metals. Valvular bioprostheses, on the other hand, typically are fabricated from either porcine aortic valves or bovine pericardium.
Prostheses derived from natural tissues are preferred over mechanical devices because of certain clinical advantages. For example, tissue-derived prostheses generally do not require routine anticoagulation. Moreover, when tissue-derived prostheses fail, they usually exhibit a gradual deterioration which can extend over a period of months or even years. Mechanical devices, on the other hand, typically undergo catastrophic failure.
Although any prosthetic device can fail because of mineralization, such as calcification, this cause of prosthesis degeneration is especially significant in tissue-derived prostheses. Indeed, calcification has been stated to account for 50 percent of failures of cardiac bioprosthetic valve implants in children within 4 years of implantation. In adults, this phenomenon occurs in approximately 20 percent of failures within 10 years of implantation. See, for example, Schoen et al.,
J. Lab. Invest.,
52, 523-532 (1985). Despite the clinical importance of the problem, the pathogenesis of calcification is not completely understood. Moreover, there apparently is no effective therapy known at the present time.
The origin of mineralization, and calcification in particular, has, for example, been shown to begin primarily with cell debris present in the tissue matrices of bioprosthetic heart valves, both of pericardial and aortic root origin. Bioprosthetic cross-linked tissue calcification has also been linked to the presence of alkaline phosphatase that is associated with cell debris and its possible accumulation within implanted tissue from the blood. Still others have suggested that mineralization is a result of phospholipids in the cell debris that sequester calcium and form the nucleation site of apatite (calcium phosphate).
Regardless of the mechanism by which mineralization in bioprostheses occurs, mineralization, and especially calcification, is the most frequent cause of the clinical failure of bioprosthetic heart valves fabricated from porcine aortic valves or bovine pericardium. Human aortic homograft implants have also been observed to undergo pathologic calcification involving both the valvular tissue as well as the adjacent aortic wall albeit at a slower rate than the bioprosthetic heart valves. Pathologic calcification leading to valvular failure, in such forms as stenosis and/or regeneration, necessitates re-implantation. Therefore, the use of bioprosthetic heart valves and homografts have been limited because such tissue is subject to calcification. In fact, pediatric patients have been found to have an accelerated rate of calcification so that the use of bioprosthetic heart valves is contraindicated for this group.
Several possible methods to decrease or prevent bioprosthetic heart valve mineralization have been described in the literature since the problem was first identified. Generally, these methods involve treating the bioprosthetic valve with various substances prior to implantation. Among the substances reported to work are sulfated aliphatic alcohols, phosphate esters, amino diphosphonates, derivatives of carboxylic acid, and various surfactants. Nevertheless, none of these methods have proven completely successful in solving the problem of post-implantation mineralization.
Currently there are no bioprosthetic heart valves that are free from the otential to mineralize in vivo. Although there is a process employing amino oleic acid (AOA) as an agent to prevent calcification in the leaflets of porcine aortic root tissue used as a bioprosthetic heart valve, AOA has not been shown to be effective in preventing the mineralization of the aortic wall of such devices. As a result, such devices may have to be removed.
Accordingly, there is a need for providing long-term calcification resistance for bioprosthetic heart valves and other tissue-derived implantable medical devices which are subject to in vivo pathologic calcification.
SUMMARY OF THE INVENTION
The present invention provides a method for reducing the level of mineralization of tissue in a tissue-derived implantable medical device. Preferably, the method reduces the level of bioprosthetic valvular mineralization, and in particular bioprosthetic valvular pathologic calcification.
In a preferred embodiment of the invention, the tissue-derived implantable medical device treated by a method of the invention exhibits improved anti-mineralization properties, and/or longer term resistance to in vivo pathologic calcification than provided by other methods of reducing and/or preventing mineralization. Although not wishing to be bound by theory, the method of the invention may inhibit enzymes and other proteins (e.g., calcium binding proteins) that are present within the tissue from performing their specific functions. These proteins are principally involved in phosphate and calcium metabolism and may be important in the formation of calcium phosphate, the major component of mineralized tissue. Treatment by the method of the invention may effectively inactivate such protein activity and reduce the accumulation of phosphates and/or calcium in the tissue after implantation, thus reducing the initiation of the mineralization process.
In another preferred embodiment, the method provides treatments performed on tissue during a method of making a tissue-derived implantable medical device. These treatment steps can be performed immediately upon excision of tissue from an animal, for example, or subsequent to incorporating the tissue into the device. A preferred device is a bioprosthetic heart valve. The method reduces mineralization on valvular leaflets and supporting structures, such as the aortic walls, after the device is implanted into patients. Reduction of mineralization of both valvular leaflets and aortic walls may allow for improved performance of the device over the duration of the implant.
In one embodiment, the present invention provides a method of making a tissue-derived implantable medical device. The method involves contacting the tissue with a composition that includes at least one oxidizing agent prior to implantation of the medical device. Preferably, the method further includes rinsing the tissue to remove at least a portion of, and preferably substantially all of, the oxidizing agent. Preferably, the tissue-derived implantable medical device is a heart valve, which can be derived from porcine aortic root tissue, bovine aortic root tissue, porcine pericardium, bovine pericardium, bovine veins, porcine veins, bovine arteries, or porcine arteries.
Preferably, the oxidizing agent is selected from the group of sodium hypochlorite, sodium bromate, sodium hydroxide, sodium iodate, sodium periodate, performic acid, periodic acid, potassium dichromate, potassium permanganate, chloramine T, peracetic acid, and combinations thereof. More preferably, the oxidizing agent is selected from the group of sodium hypochlorite, performic acid, periodic acid, peracetic acid, and combinations thereof.
The composition that includes an oxidizing agent preferably further includes at least one chelating agent. Examples of suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), citric acid, salts thereof, and combinations thereof.
The composition that includes an oxidizing agent also preferably further includes a buff
Berry Thomas G.
Latham Daniel W.
Medtronic Inc.
Tate Christopher R.
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