Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Heart valve – Specific material for heart valve
Reexamination Certificate
2000-01-10
2002-10-29
O'Connor, Cary E. (Department: 3732)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Heart valve
Specific material for heart valve
C623S023720
Reexamination Certificate
active
06471723
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to medical articles including an aldehyde crosslinked tissue. In particular, the invention relates to fixed tissue with reduced cytotoxicity and reduced susceptibility to calcification.
Various medical articles have been designed particularly for contact with a patient's bodily fluids. This contact can be sufficiently long such that surface interactions between the medical article and the patient's blood and/or tissue become significant. For example, the host interaction with the medical article can lead to degradation, such as calcification of the medical article. Relevant medical articles include, for example, catheters and prostheses.
Catheters include percutaneous devices that penetrate the skin to provide access to a bodily system. Prostheses, i.e., prosthetic devices, are used to repair or replace damaged or diseased organs, tissues and other structures in humans and animals. Prostheses must be generally biocompatible since they are typically implanted for extended periods of time. Prostheses can be constructed from natural materials, synthetic materials or a combination thereof.
Bioprosthetic heart valves from natural materials were introduced in the early 1960's. Bioprosthetic heart valves typically are derived from pig aortic valves or are manufactured from other biological materials such as bovine pericardium. Xenograft heart valves, i.e., heart valves originating from a donor of a species different from the species of the recipient, are typically fixed with glutaraldehyde prior to implantation to reduce the possibility of immunological rejection. Glutaraldehyde reacts to form covalent bonds with free functional groups in proteins, thereby chemically crosslinking nearby proteins.
The importance of bioprosthetic animal heart valves as replacements for damaged or diseased human heart valves has resulted in a considerable amount of interest in the long term performance of these valves and, in particular, in the effects of calcification on these xeno-transplants. Calcification, i.e., the deposit of calcium salts, especially calcium phosphate (hydroxyapatite), can occur in and on some materials of a medical article while contacting the patient's bodily fluids or tissue. Calcification can affect the performance and structural integrity of medical articles constructed from these materials, especially over extended periods of time. For example, calcification is the primary cause of clinical failure of bioprosthetic heart valves made from porcine aortic valves or bovine pericardium. Calcification can be particularly severe at stress points, such as where suture passes through tissue.
Generally, bioprosthetic heart valves begin failing after about seven years following implantation, and few bioprosthetic valves remain functional after 20 years. Replacement of a degenerating valve prosthesis subjects the patient to additional surgical risk, especially in the elderly and in situations of emergency replacement. While failure of bioprostheses is a problem for patients of all ages, it is particularly pronounced in younger patients. Over fifty percent of bioprosthetic valve replacements in patients under the age of 15 fail in less than five years because of calcification. Other prostheses made from natural and/or synthetic materials may also display clinically significant calcification.
As a result, there is considerable interest in preventing the deposit of calcium on implanted biomaterials, especially heart valves. Research on the prevention of calcification has focused to a considerable extent on the pretreatment of the biomaterial prior to implantation. Detergents (e.g., sodium dodecyl sulfate), toluidine blue or diphosphonates have been used to pretreat tissues in an attempt to decrease calcification by reducing calcium nucleation. Within a relatively short time, these materials tend to wash out of the bioprosthetic material into the bodily fluids surrounding the implant, limiting their effectiveness. A significant advance toward reducing calcification of bioprostheses was the determination that Al
+3
cations and other multivalent cations inhibit calcification.
Other approaches to reducing calcification have employed a chemical process in which at least some of the reactive glutaraldehyde moieties are inactivated. Still other approaches have included development of alternative fixation techniques, since evidence suggests that the fixation process itself may contribute to calcification and the corresponding mechanical deterioration. In addition, since nonviable cells present in transplanted tissue are sites for calcium deposition, various processes have been developed to remove cellular material from the collagen-elastin matrix of the tissue prior to implantation.
Another major disadvantage of tissue based prostheses is the failure of such devices to be self-maintaining. Long term durability is enhanced by the ability of viable cells to populate the implanted tissue and to carry out maintenance functions. The importance of viable cells has been studied in the context of homograft transplants, i.e., transplants from one member of a species to another member of the same species. Proper homograft preservation can maximize the number of viable cells remaining in the tissue as determined by matrix protein synthesis. Preservation techniques that do not promote cell survival, such as long term storage at 4° C., are associated with reduced in vivo durability and increased reoperation rates.
Thus cell ingrowth into prosthetic tissue material can decrease the prevalence of calcification and reintroduce some degree of self maintenance. However, aldehyde crosslinking tends to make the tissue cytotoxic. This cytotoxicity appears to be due to unreacted aldehyde functional groups. While processing approaches to reduce calcification may reduce the level of cytotoxicity, residual cytotoxicity remains a problem with respect to colonization of the crosslinked tissue by mammalian cells both in vitro in a cell culture and in vivo in a patient following implantation.
SUMMARY OF THE INVENTION
In a first aspect, the invention pertains to a prosthetic tissue comprising a chemically crosslinked protein matrix having no detectable cytotoxicity without any added growth hormones.
In a further aspect, the invention pertains to a prosthetic tissue comprising a protein matrix crosslinked with a multifunctional aldehyde having an extractable residual aldehyde compound concentration of no more than about 5×10
−4
moles aldehyde per gram of dry tissue.
Moreover, the invention pertains to a prosthetic tissue comprising adducts of aldehyde groups and inorganic sulfur-oxygen groups.
In addition, the invention pertains to a prosthetic tissue comprising adducts of aldehyde groups and ammonia/ammonium groups and adducts of aldehyde groups and sulfur-oxygen groups.
In another aspect, the invention pertains to a method for reducing residual reactive aldehyde groups associated with an aldehyde crosslinked tissue. The method includes contacting an aldehyde crosslinked tissue with an inorganic sulfur-oxygen compound.
Furthermore, the invention pertains to a composition comprising inorganic sulfur-oxygen group and an amine.
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Ashworth Paul Edward
Johnson Andrea L.
Kelly Sheila Jeanne
McTavish Daniel Paul
Ogle Matthew Frank
Dardi Peter S.
Finucane Hallie A.
O'Connor Cary E.
Patterson Thuente Skaar & Christensen P.A.
St. Jude Medical Inc.
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