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

Ailsa J. Dalgliesh, Mojtaba Parvizi, Manuela Lopera-Higuita, Jeny Shklover, Leigh Griffiths

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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. Statement of Significance: 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.

Original languageEnglish (US)
JournalActa Biomaterialia
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Immune Tolerance
Biocompatible Materials
Biomaterials
Grafts
Scaffolds
Extracellular Matrix
Transplants
Antigens
Adaptive Immunity
Heterophile Antigens
Immune system
Glutaral
Immune System
Tissue
Proteins
Bioprosthesis
Heart Valves
Tissue Engineering
Scaffolds (biology)
Humoral Immunity

Keywords

  • Antigenicity
  • Bovine pericardium
  • Immune response

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

Cite this

Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds. / Dalgliesh, Ailsa J.; Parvizi, Mojtaba; Lopera-Higuita, Manuela; Shklover, Jeny; Griffiths, Leigh.

In: Acta Biomaterialia, 01.01.2018.

Research output: Contribution to journalArticle

@article{c1d157f6946643ed92e423cd96e1d32c,
title = "Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds",
abstract = "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. Statement of Significance: 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.",
keywords = "Antigenicity, Bovine pericardium, Immune response",
author = "Dalgliesh, {Ailsa J.} and Mojtaba Parvizi and Manuela Lopera-Higuita and Jeny Shklover and Leigh Griffiths",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.actbio.2018.08.016",
language = "English (US)",
journal = "Acta Biomaterialia",
issn = "1742-7061",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds

AU - Dalgliesh, Ailsa J.

AU - Parvizi, Mojtaba

AU - Lopera-Higuita, Manuela

AU - Shklover, Jeny

AU - Griffiths, Leigh

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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. Statement of Significance: 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.

AB - 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. Statement of Significance: 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.

KW - Antigenicity

KW - Bovine pericardium

KW - Immune response

UR - http://www.scopus.com/inward/record.url?scp=85052321822&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052321822&partnerID=8YFLogxK

U2 - 10.1016/j.actbio.2018.08.016

DO - 10.1016/j.actbio.2018.08.016

M3 - Article

C2 - 30130615

AN - SCOPUS:85052321822

JO - Acta Biomaterialia

JF - Acta Biomaterialia

SN - 1742-7061

ER -