Sterilization

Details Sterilization Sterilization

2000-08-09

2003-02-18

Warden, Sr., Robert J. (Department: 1744)

Chemical apparatus and process disinfecting, deodorizing, preser

Process disinfecting, preserving, deodorizing, or sterilizing

Using disinfecting or sterilizing substance

C422S032000, C422S040000, C422S292000, C530S356000, C530S402000, C435S001100, C623S002220, C623S011110, C623S066100, C623S915000, C623S920000

Reexamination Certificate

active

06521179

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to sterilization and more specifically to sterilization processes for use with biological materials, such as organ replacements and homografts, which processes exhibit efficacy against difficult-to-kill bacteria and bacterial spores wherein the effect upon the physical properties of the biological material being sterilized is controllable.
BACKGROUND OF THE INVENTION
Sterilization techniques are widely used and important in industries such as food processing and health care. Saturated steam at temperatures above 110° C. has frequently been used to destroy microorganisms, such as microbial spores. Certain articles, particularly those used for health care which consist of or incorporate biological tissue, cannot withstand the temperatures and moisture of steam sterilization, and oftentimes such articles are also considered not to be suitable for sterilization by ionizing radiation. Gaseous sterilants have been developed which function at relatively low temperatures and thus may offer an attractive alternative. Ethylene oxide is a commonly used gaseous sterilant which is often used for medical product sterilization; however, in certain instances, the presence of residual ethylene oxide is considered to be detrimental, even in small quantities. Allografts and other implants containing biological tissue have been sterilized by immersion in antibiotic mixtures, but such processes are very expensive and do not destroy certain bacterial spores and viruses. Accordingly, improved methods of sterilization for medical products that include biological tissue have continued to be sought which would not otherwise significantly alter the physical characteristics of the medical products, particularly allografts and xenografts for which the physical effect upon the medical products should be closely controlled.
Our U.S. Pat. No. 5,911,951 describes an excellent sterilization process for biological tissue by treating with a water-soluble carbodiimide, such as EDC, in the presence of a lower alkanol, such as isopropanol.
SUMMARY OF THE INVENTION
It has now been found that medical products which include biological tissue, e.g. allografts and xenografts is such as replacement organs, ligaments, tendons, vascular grafts and the like, as well as acellular material including items made of extracted collagen or using a process such as that taught in U.S. Pat. No. 4,776,853, can be effectively sterilized by treatment with a bactericidal coupling agent of the type known to create amide linkages between amines and carboxyl moieties in a manner so that there is either no significant change or a closely controllable change in the physical character of the biological material being sterilized. Sterilization treatment is preferably carried out at a temperature above ambient in a buffered solution, that may optionally contain isopropyl alcohol or an equivalent alcohol in an amount effective to promote penetration of said coupling agent into the cells of the microorganisms. The sterilization treatment is carried out in the presence of protecting agents that complex with and protect either residual amine groups or residual carboxyl groups on the proteinaceous biological material that is being treated, thereby carefully controlling the amount of cross-linking thereof so as not to undesirably change the physical characteristics of the resultant biological material. The residuals from such treatment are nontoxic, biocompatible, and water-soluble, so that they can easily be washed off the tissue before packaging or implantation in a human body.
It was surprising to find that biological tissue can be effectively sterilized using coupling agents that create amide bonds, while at the same time either avoiding the occurrence of any significant cross-linking within the biological material itself or alternatively carefully controlling the amount of cross-linking which occurs.
In one particular manner, the invention provides a process for sterilization of biological tissue material, which process comprises treating such material with an aqueous solution containing (a) an amount of a water-soluble coupling agent capable of creating amide bonds that is effective to achieve sterilization and (b) an amount of a protecting agent which is effective to complex with potentially reactive amine or carboxyl moieties on the biological tissue material so as to deter such complexed moieties from taking part in an amide-forming cross-linking reaction and thereby limit the amount of cross-linking, and maintaining such treatment for a time and at a temperature which is sufficient to achieve penetration of said coupling agent into the cells of microorganisms carried by such material and effectively kill such microorganisms.
In another particular manner, the invention provides a process for sterilization of biological tissue, which process comprises treating such material with a protecting agent which is effective to complex with potentially reactive amine or carboxyl moieties on the biological tissue material so as to deter such complexed moieties from taking part in an amide-forming cross-linking reaction and thereby limit the amount of cross-linking, treating such material with a water-soluble coupling agent capable of creating amide bonds that is effective to achieve sterilization, and maintaining such treatment with said coupling agent for a time and at a temperature which is sufficient to achieve penetration of said coupling agent into the cells of microorganisms carried by such material and effectively kill such microorganisms.
In a further particular manner, the invention provides a process of sterilization of biological tissue that has been rendered acellular either before or after cross-linking or that has not been cross-linked.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Medical products which consist of or incorporate biological tissue require sterilization prior to packaging or prior to implantation into a patient, and for certain products, the sterilant should be one that leaves no undesirable residue and that either does not change the physical characteristics of the medical product or only changes it in a carefully controllable manner. For example, for allografts, changes in the structure or the rigidity of the biological tissue are considered detrimental and to be avoided. Allografts, sometimes referred to as homografts, include replacement organs and connective tissues, e.g. cartilage, tendons, ligaments, bone, and muscle tissue, and are generally desirably transplanted into a receiving patient without change in structure or character. On the other hand, certain medical products which include animal tissue, such as prosthetic tissue valves for heart valve replacement, e.g. porcine aortic valves or tissue valves constructed from bovine pericardium, may have been previously fixed, i.e. cross-linked, to carefully provide them with a character and flexibility desired for long term operation. Accordingly, any change to such carefully tailored physical characteristics, as by rigidifying the tissue, may be considered to constitute an undesirable alteration of the product. Still other tissue-engineered products may desirably have a variable duration of resorption in instances where it is desired that the body remodel the product following implantation.
In the foregoing context, once it was discovered that amide-creating coupling agents could be effectively used to sterilize articles by completely inactivating microorganisms and spores, it was decided to investigate if such a sterilization treatment could be adapted to sterilizing allografts and other such engineered tissue products that include mammalian biological tissue. It was surprisingly found that the potentially accompanying undesirable cross-linking of the proteinaceous biological tissue could be minimized or carefully controlled by carrying out the sterilization treatment in the presence of protective agents that would temporarily or permanently complex with the potentially reactive amine or carboxyl moieties on the prot

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