Chemical apparatus and process disinfecting – deodorizing – preser – Process disinfecting – preserving – deodorizing – or sterilizing – Using direct contact with electrical or electromagnetic...
Reexamination Certificate
1994-03-04
2001-03-20
Thornton, Krisanne (Department: 1744)
Chemical apparatus and process disinfecting, deodorizing, preser
Process disinfecting, preserving, deodorizing, or sterilizing
Using direct contact with electrical or electromagnetic...
C422S023000, C422S036000, C435S001100, C623S002220
Reexamination Certificate
active
06203755
ABSTRACT:
TECHNICAL FIELD
The invention involves sterilized biological tissues and methods for sterilizing biological tissues.
BACKGROUND OF THE INVENTION
Surgical implantation of tissue is utilized to replace and/or repair human tissues. For example, hereditary defects, disease, and/or trauma may damage tissues such that replacement and/or repair is desirable. These implantable tissues may be provided by individual human donors. However, because of the scarcity of appropriate human donors, non-human tissues have been increasingly employed instead. Such biological tissues have been used to replace heart valves, ligaments, tendons and skin, among other tissues.
Biological tissues derived from non-human or non-self sources may pose formidable problems to the new recipient. For example, the recipient's immune system may react to the implanted tissue and form an immune response, potentially leading to rejection of the implanted tissue. Thus, the new tissue may become ineffective and/or exhibit poor durability once implanted.
Conventionally, glutaraldehyde has been used to address some of these problems and to stabilize the tissue against in vivo enzymatic degradation. Additionally, glutaraldehyde has been used as a sterilizing agent to inhibit the infectivity of implant tissue. Glutaraldehyde cross-links proteins rapidly and effectively, particularly proteins such as collagen. This treatment increases resistance to proteolytic cleavage and hence increases resistance to enzymatic degradation.
In addition to crosslinking with glutaraldehyde, it is also well known to sterilize the crosslinked tissue with gamma radiation and the like prior to storage of the biological tissue.
Gamma radiation, and similar sterilization protocols, transfers energy to material primarily by Compton scattering i.e., scattering involving elastic collisions between incident photons and unbound (or weakly bound) electrons in which the incident energy is shared between the scattered electron and the deflected photon. These electrons recoil a short distance as unbound electrons, giving up energy to the molecular structure of the material as they collide with other electrons, causing ionization and free-radical formation. The scattered gamma ray carries the balance of the energy as it moves off through the material, possibly to interact again with another atomic electron. Since the probability for Compton scattering is low, gamma rays typically penetrate relatively deeply into the tissue before scattering occurs. Accordingly, gamma rays deposit energy in material over relatively large volumes so that penetration is typically high (typically greater than 50 cm in unit-density material) but dose rates are typically low (typically about a maximum of 20 kGy/hr). See FIG.
1
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Most techniques for sterilizing biological tissues produce undesirable results in the material, but the undesirable results may be more prominent when gamma radiation is used. Such undesirable results include but are not limited to the formation of radicals, hydrogen, and low-molecular-weight hydrocarbons; increased unsaturation; discoloration; and oxidation. Furthermore, gamma radiation typically requires a low dose rate in combination with a high exposure period, and degrades the structure of most conventional packaging materials.
Biological tissues prepared by the prior art methods suffer from a number of disadvantages, which limits their use in implantation, particularly human implantation. First, the use of some chemical sterilizing agents e.g., glutaraldehyde, increases the risk that a toxic response will be evoked in sensitive individuals, even after thorough rinsing of the tissue prior to implantation. Second, the use of certain sterilizing agents requires that the tissue be sterilized prior to packaging, thus necessitating a packaging step which must be carried out under stringent aseptic conditions. Third, gamma radiation can degrade polymeric materials employed in packaging by facilitating damaging oxidative reactions of polymers. Fourth, because gamma radiation typically involves relatively low dose rates, correspondingly long periods of exposure to effect sterilization may be necessary.
Thus there is an unaddressed need in the art for a method of sterilizing biological tissues that minimizes the possibility of immune rejection. Additionally, there exists a long-felt need for a method of sterilizing that does not necessitate an aseptic packaging step. Further, there is a need in the art for a method of sterilizing tissues which does not degrade the polymeric materials employed in packaging sterilized biological tissues. There is also a need for a method of sterilizing biological tissues that is quick, efficient, and results in a biological tissue with enhanced performance characteristics.
SUMMARY OF THE INVENTION
The present invention encompasses sterilized biological tissues and methods of sterilizing biological tissues which reduce or eliminate the disadvantages noted above.
In accordance with the present invention, biological tissues are treated by exposing the tissue to E-beam radiation sufficient to effect sterilization. Additionally, the present invention provides a biological tissue sterilized by E-beam radiation, with the resulting biological tissue exhibiting enhanced performance characteristics. The methods and tissues according to the present invention have the added advantage of reduced risk of infectivity, and eliminates the need for aseptic handling protocols. Further, the methods and tissues of the present invention, which use fewer reagents and/or require less processing, provide for lower costs in labor, reagents, time and personnel. E-beam radiation sterilization is effective in obviating the need for toxic sterilizing chemicals. Moreover, the amount of radiation required for E-beam sterilization does not significantly degrade the biological tissue, thus providing a more durable transplantable tissue.
There are a large number of characteristics that distinguish accelerated electrons from gamma rays:
Source of Radiation. Gamma rays are emitted by the decay of Cobalt-60. E-beams are produced by accelerating electron systems such as linear accelerators, Dynamitrons, and Van de Graaff generators.
Dose Rate. The dose rate for gamma radiation is approximately 110 grays per minute and the dose rate of E-beam is approximately 7800 grays per minute. Consequently, exposure times are dramatically greater for gamma radiation, which requires low doses over an extended period to effect sterilization. In contradistinction to gamma radiation, the high dose rates involved in E-beam irradiation promote diffusion of oxygen into biological tissue at a rate insufficient to participate in free radical formation reactions, such as those which might contribute to tissue and polymer degradation. This is particularly advantageous in those embodiments which include placing the biological tissue in a container prior to irradiation, since polymer degradation in both the tissue and the container may be minimized.
Furthermore, the high dose rate of E-beams relative to gamma rays permits a higher processing rate of sterilization, commonly an order of magnitude higher. For example, the sterilization period may be a matter of minutes for E-beam treatment, in contrast to the hours or more for gamma radiation treatment. Yet despite the higher dose rate, the present process does not result in significant degradation of biological tissue during the sterilization process.
Penetration. In relative terms, gamma radiation penetrates approximately ten times further into materials than 10 MeV electrons in the same material. Because the probability for electron-electron and electron-nuclear scattering may be high (relative to Compton scattering), 10 MeV E-beams typically penetrate approximately 5 cm in unit-density material before losing their energy. Thus, the power in the beam is typically deposited within a narrow range in the material and concentrated within the width of the beam. This results in high dose rate and low penetration (300 kGy per pulse, with an
Dardi Peter S.
St. Jude Medical Inc.
Thornton Krisanne
Westman Champlin & Kelly
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