Crosslinked human or animal tissue products and their methods of manufacture and use
Inventors
Mezger, W. Jerry • Myers, Keith E.
Assignees
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Publication Number
US-9220808-B2
Publication Date
2015-12-29
Expiration Date
Abstract
Degradable bioprostheses made of collagen-based material having amine-based and ester-based crosslinks are provided, as are methods for their formation and use. Some embodiments of the present invention are directed towards a method of controlling the ratio of amine-based crosslinks to ester-based crosslinks within a collagen-based material to provide a tailorably crosslinked collagen-based material. Some embodiments provide a method of making a degradable bioprosthesis involving controlling crosslinking to afford a degradable bioprosthesis that is partially crosslinked. By controlling the ratio of amine-based to ester-based crosslinks, by controlling the level of crosslinking, or by controlling both of these features, degradable bioprostheses with tailored degradation rates can be synthesized. Some embodiments of degradable bioprostheses have degradation rates that are tailored to allow their use in particular medical applications. Some embodiments are directed towards methods of use degradable bioprostheses in wound healing, tissue repair, and tissue supplementation.
Core Innovation
The disclosed invention relates to degradable collagen-based bioprostheses formed from a collagen-based material that is tailorably crosslinked to control degradation. The bioprosthesis includes amine-based crosslinks and ester-based crosslinks, produced using diepoxides as crosslinking agents.
Crosslinking is achieved by contacting the collagen-based material with buffered solutions at distinct pH ranges, including a first buffered solution with a pH between about 8.0 to about 10.5 and a second buffered solution with a pH between about 3.0 to about 5.5. This two-step buffered pH exposure produces a tailorably crosslinked collagen-based material and provides a degradable bioprosthesis with measured degradation behavior in pronase digestion assay.
The document further characterizes the relationship between crosslinking and degradation using measured outcomes such as shrinkage temperature (Ts) and protease resistance. It also describes example pH modulation from high pH to low pH during crosslinking and reports that such a pH shift enables faster bioresorbtion, as reflected in measured degradation rates.
Claims Coverage
The provided independent claims cover methods of making a degradable bioprosthesis from a collagen-based material using two-step buffered diepoxide crosslinking at different pH values, producing a material with both amine-based and ester-based crosslinks and a defined pronase digestion degradation rate. Across the independent claims, the inventive features are organized around two buffered pH exposures with diepoxide crosslinking agents and resulting degradation performance measured in the pronase digestion assay.
Two-step buffered diepoxide crosslinking to provide tailorably crosslinked collagen
Providing a collagen-based material; contacting the collagen-based material with a first buffered solution with a pH between about 8.0 to about 10.5 for a first period of time to provide a treated collagen-based material; contacting the treated collagen-based material with a second buffered solution with a pH between about 3.0 to about 5.5 for a second period of time to provide a tailorably crosslinked collagen-based material; and isolating the tailorably crosslinked collagen-based material to provide the degradable bioprosthesis, wherein the first and second crosslinking agents are diepoxides.
Amine-based and ester-based crosslinks with pronase digestion degradation-rate constraint
Providing a degradable bioprosthesis that comprises amine-based crosslinks and ester-based crosslinks, wherein the degradable bioprosthesis has a degradation rate between about 0.2% to about 1.0% per hour during the first 24 hours of exposure to a pronase digestion assay.
Different buffered pH levels where first pH is higher than second pH for diepoxide crosslinking
Providing a collagen-based material; contacting the collagen-based material with a first buffered solution having a first pH greater than about 8.0 for a first period of time, wherein the first buffered solution comprises a concentration of a first diepoxide crosslinking agent; contacting the treated collagen-based material with a second buffered solution having a second pH for a second period of time, wherein the first pH is higher than the second pH, and wherein the second buffered solution comprises a concentration of a second diepoxide crosslinking agent; and isolating the tailorably crosslinked collagen-based material to provide the degradable bioprosthesis.
Taken together, the independent claims require two buffered pH treatments using diepoxide crosslinking agents to form a tailorably crosslinked collagen-based bioprosthesis containing both amine-based and ester-based crosslinks, with a pronase digestion degradation rate between about 0.2% and about 1.0% per hour during the first 24 hours of exposure.
Stated Advantages
Tunable degradable performance, characterized by a degradation rate between about 0.2% and about 1.0% per hour during the first 24 hours of exposure to a pronase digestion assay.
Provides faster bioresorbtion after a pH shift during crosslinking, as reflected in measured degradation rates.
Documented Applications
Wound healing.
Tissue repair and supplementation.
Use of partially crosslinked skin substitutes.
Use of surgical meshes.
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