Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds

[Display omitted] Antigenicity remains the primary barrier towards expanding the use of unfixed xenogeneic biomaterials in clinical applications. An unfixed xenogeneic biomaterial devoid of antigenicity, with maintained structural and mechanical integrity, has potential to overcome the limitations o...

Full description

Saved in:
Bibliographic Details
Published in:Acta biomaterialia 2018-10, Vol.79, p.253-264
Main Authors: Dalgliesh, Ailsa J., Parvizi, Mojtaba, Lopera-Higuita, Manuela, Shklover, Jeny, Griffiths, Leigh G.
Format: Article
Language:English
Subjects:
Adaptive Immunity
Animals
Antigenicity
Antigens
Antigens - metabolism
Betaine - analogs & derivatives
Betaine - chemistry
Biocompatibility
Biomaterials
Biomedical materials
Bovine pericardium
Cattle
Collagen - metabolism
Disruption
Extracellular matrix
Extracellular Matrix - metabolism
Glutaraldehyde
Heart
Heart valves
Heterografts - immunology
Humans
Immune response
Immune response (humoral)
Immune system
Immune Tolerance
Immunity, Humoral
Immunological tolerance
Implantation
Innate immunity
Lipids - chemistry
Lipophilic
Molecular structure
Pericardium - metabolism
Proteins
Surgical implants
Therapeutic applications
Tissue engineering
Tissue Scaffolds - chemistry
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] Antigenicity remains the primary barrier towards expanding the use of unfixed xenogeneic biomaterials in clinical applications. An unfixed xenogeneic biomaterial devoid of antigenicity, with maintained structural and mechanical integrity, has potential to overcome the limitations of current clinically utilized glutaraldehyde-fixed xenogeneic biomaterials, such as heart valve bioprostheses. Unfortunately, the threshold level of residual antigenicity necessary to overcome graft-specific immune responses in unfixed xenogeneic tissue has yet to be determined. Furthermore, little information is known regarding the extent to which in vitro disruption of native ECM properties, resulting from decellularization or antigen removal procedures, are tolerated following in vivo implantation. This manuscript demonstrates that humoral adaptive immune responses are more sensitive to residual xenogeneic biomaterial antigen content than are cell-mediated adaptive responses. Critically, the threshold for tolerable residual antigenicity is identified, with removal of ≥92% of lipophilic antigens required to reduce adaptive immune responses to levels equivalent to glutaraldehyde fixed tissue. Finally, the results demonstrated that the innate immune system tolerates minor changes in protein organization provided that molecular structure is maintained. Antigen removed xenogeneic biomaterials achieving these in vitro success criteria induce in vivo adaptive and innate tolerance, while modulating pro-regenerative constructive remodeling. Removal of antigenic components from candidate xenogeneic biomaterials is the primary success criteria for development of extracellular matrix (ECM) scaffolds in tissue engineering applications. Currently, the threshold level of residual biomaterial antigenicity required to overcome recipient graft-specific adaptive immune responses is unknown. Additionally, the extent to which the innate immune response tolerates changes to the native ECM, resulting from the ECM scaffold production process, has yet to be determined. This manuscript not only establishes the threshold for tolerable residual antigenicity, but also demonstrates that deviations in protein organization are tolerated by the innate immune system, provided macromolecular structure remains intact. In doing so, we provide the foundation of an immunologically-acceptable unfixed xenogeneic biomaterial for use in clinical applications.
ISSN:1742-7061
1878-7568
DOI:10.1016/j.actbio.2018.08.016