Viable Gal Knock-Out Sheep for Implant Antigen Screening
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Solution Overview
Problem
The implantation of foreign biological organs or tissues in humans often leads to rejection due to the immune system recognizing them as foreign, with existing screening methods being insufficient and immunosuppressive drugs having negative side effects, as exemplified by the catastrophic failure of acellular porcine heart valves due to residual Gal antigen.
Innovation Solution
Development of viable galactosyltransferase (Gal) knock-out sheep lacking the alpha-1,3-galactosyltransferase (GGTA1) gene, which are used to screen biological implants for Gal antigen presence by implanting them and detecting antibody-mediated inflammatory responses, ensuring Gal-free implants for human use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunosuppressive drugs are used to reduce implant rejection risk, then the immune response against foreign implants is suppressed, but cancer and infection rates increase
Solution Approach 1:
The patent extracts and removes the harmful Gal antigen from the implant by using galactosidase enzyme treatment during the decellularization process. This eliminates the specific antigen that triggers anti-Gal antibody production, allowing implants to be used without immunosuppressive drugs while avoiding cancer and infection risks associated with immunosuppression.
Solution Approach 2:
The patent changes the chemical composition parameters of the implant by treating it with galactosidase enzyme to remove Gal antigens. This biochemical modification alters the immunogenicity of the implant, making it compatible with human recipients without requiring immunosuppressive therapy.
2Ease of manufacture
If standard animal models are used for antigen screening, then the screening process is simple and cost-effective, but the results may be insufficient when antigens are not recognized by the animal model's immune system
Solution Approach 1:
The patent introduces a transgenic animal model that serves as an intermediary between standard animal models and human recipients. These animals express human-like immune responses to Gal antigens, acting as a bridge that provides more accurate predictive value for human implant compatibility while maintaining the simplicity of animal-based screening.
3Stability of the object's composition
If decellularization procedures are performed to remove cellular debris, then the implant structure is preserved, but residual Gal antigen may remain causing immune valve failure
Solution Approach 1:
The patent extends the decellularization process by adding a galactosidase enzyme treatment step that continuously acts on the implant to remove residual Gal antigens. This continuous biochemical action ensures complete antigen removal while preserving the structural integrity already established by mechanical decellularization.
Solution Approach 2:
The patent converts the harmful residual Gal antigen into a benefit by using it as a target for galactosidase enzyme treatment. The enzyme specifically recognizes and removes the Gal antigen, transforming the problematic residual component into a controlled removal process that enhances implant compatibility.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The Gal knock-out sheep model effectively identifies Gal antigen in implants, reducing the risk of immune rejection and prolonging the durability of biological implants by minimizing structural valve deterioration and reoperations.
Implementation Method 1
The viable Gal knock-out sheep, upon contact of immune cells of the sheep with Gal, produces Gal antibodies
Data Source
AI summary
Provided herein is the first viable galactosyltransferase (Gal) knock-out sheep having a deletion or mutation of alpha-1,3-galactosyltransferase (GGTA1) gene and methods of making the same. Also provided are methods of screening a biological implant for stimulation of an antibody-mediated inflammatory response to a Gal antigen by implanting the biological implant into a recipient Gal knock-out animal and detecting signs of antibody-mediated inflammatory response in the recipient Gal knock-out animal. Further provided is a method of implanting a biological implant into a human subject by screening a first biological implant for signs of antibody-mediated inflammatory response in a recipient Gal knock-out animal and, upon detecting minimal or no signs of antibody mediated inflammatory response in the recipient Gal knock-out animal, implanting a second biological implant into the human subject, wherein the second biological implant is comparable to the first biological implant.