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Cited by 112Tissue Engineering and Regenerative MedicineXenotransplantation and immune responseOrgan and Tissue Transplantation Research

In vivo xenogeneic scaffold fate is determined by residual antigenicity and extracellular matrix preservation

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Wong, Maelene L., Wong, Janelle L., Vapniarsky, Natalia, Griffiths, Leigh G.·2016·Biomaterials
DOI 10.1016/j.biomaterials.2016.03.024PMC PMC5289067
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Abstract

The immunological potential of animal-derived tissues and organs is the critical hurdle to increasing their clinical implementation. Glutaraldehyde-fixation cross-links proteins in xenogeneic tissues (e.g., bovine pericardium) to delay immune rejection, but also compromises the regenerative potential of the resultant biomaterial. Unfixed xenogeneic biomaterials in which xenoantigenicity has been ameliorated and native extracellular matrix (ECM) architecture has been maintained have the potential to overcome limitations of current clinically utilized glutaraldehyde-fixed biomaterials. The objective of this work was to determine how residual antigenicity and ECM architecture preservation modulate recipient immune and regenerative responses towards unfixed bovine pericardium (BP) ECM scaffolds. Disruption of ECM architecture during scaffold generation, with either SDS-decellularization or glutaraldehyde-fixation, stimulated recipient foreign body response and resultant fibrotic encapsulation following leporine subpannicular implantation. Conversely, BP scaffolds subjected to stepwise removal of hydrophilic and lipophilic antigens using amidosulfobetaine-14 (ASB-14) maintained native ECM architecture and thereby avoided fibrotic encapsulation. Removal of hydrophilic and lipophilic antigens significantly decreased local and systemic graft-specific, adaptive immune responses and subsequent calcification of BP scaffolds compared to scaffolds undergoing hydrophile removal only. Critically, removal of antigenic components and preservation of ECM architecture with ASB-14 promoted full-thickness recipient non-immune cellular repopulation of the BP scaffold. Further, unlike clinically utilized fixed BP, ASB-14-treated scaffolds fostered rapid intimal and medial vessel wall regeneration in a porcine carotid patch angioplasty model. This work highlights the importance of residual antigenicity and ECM architecture preservation in modulating recipient immune and regenerative responses towards xenogeneic biomaterial generation.

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Crossref · 10.1016/j.biomaterials.2016.03.024

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  • Natural scaffolds undergo a positive host response in which ECM experiences lysis and releases cryptic peptides and growth factors during early degradation.

    “Opposite to FBR, natural scaffolds undergo a different positive form of host response, in which ECM experiences lysis and releases some cryptic peptides and growth factors during early degradation.”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [25]

    The Discussion (page unavailable) reports that preserved ECM architecture helped ASB-14 scaffolds avoid a foreign body response, and Results §3.4 describes regenerative responses. The paper does not describe ECM lysis during early degradation or the release of cryptic peptides and growth factors as the mechanism of that response. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • This response phase shifts macrophage polarization toward M2, angiogenesis, stem/progenitor cell migration, and regeneration.

    “This response phase has a substantial role in shifting macrophage polarization toward reconstructive phenotype (M2 macrophages), angiogenesis, stem/progenitor cell migration, and collectively, the regeneration process.”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [25]

    Results §3.4 reports M2-dominant macrophage polarization, endothelialization, cell ingrowth, and vascular regeneration with ASB-14 scaffolds. It does not identify migrating cells as stem/progenitor cells or establish angiogenesis as a distinct outcome; the findings are also specific to the scaffold model rather than a general response phase. (LLM, conf=0.86)

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  • The amount of remaining hydrophilic and hydrophobic antigens precisely correlates with the immunogenicity of dECM scaffolds, unlike the level of DNA retention.

    “Unlike the level of DNA retention, the amount of remaining hydrophilic and hydrophobic antigens precisely correlates with the immunogenicity of the dECM scaffolds [25, 46].”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [25]

    Results §3.1 and the Discussion report that removing hydrophilic and lipophilic antigens reduced graft-specific immune responses in the tested scaffolds. They do not establish a precise correlation between antigen amounts and immunogenicity. Our copy also does not compare the predictive value of antigen amounts with DNA retention; the Methods describe nucleic-acid digestion, not a DNA-retention analysis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Some cryptic peptides exhibit antimicrobial traits, resulting in low pathogen-related immunogenicity in dECM scaffolds.

    “Moreover, some cryptic peptides exhibit antimicrobial traits, resulting in low pathogen-related immunogenicity in decellularized ECM (dECM) scaffolds [25, 26].”

    From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [25]

    The Introduction and Discussion attribute reduced immune responses to xenoantigen removal and preservation of ECM architecture. Searches for cryptic peptides, antimicrobial activity, and pathogen-related immunogenicity found no passage addressing the claimed mechanism. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. [9]Galili U The [alpha]-gal epitope (Gal[alpha]1-3Gal[beta]1-4GlcNAc-R) in xenotransplantation Biochimie 83 2001 557 563 11522383

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Authors
Wong, M. L., Wong, J. L., Vapniarsky, N., & Griffiths, L. G.
Affiliations
University of California, Davis (US)
Corresponding author
Griffiths, Leigh G.
ORCID
Venue
Biomaterials
Publisher
Elsevier BV
Published
2016-06
Volume
92
Pages
1-12
ISSN
0142-9612 (ISSN-L)
DOI
10.1016/j.biomaterials.2016.03.024
PMC
PMC5289067
OpenAlex
W2299944825
Cited by
112
References
42
Citations by year
2026: 7 · 2025: 9 · 2024: 13 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 20 · 2019: 14 · 2018: 12 · 2017: 4 · 2016: 3
FWCI
12.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomaterials (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association (11SDG4980023)
  • NIH (R01HL115205)
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
  • Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
Keywords
bovine pericardium, extracellular matrix architecture, antigen removal, glutaraldehyde fixation, decellularization, foreign body reaction, fibrotic encapsulation, graft calcification, immune rejection
MeSH terms
Animals, Biocompatible Materials, Calcification, Physiologic, Cattle, Collagen, Extracellular Matrix, Foreign-Body Reaction, Pericardium, Rabbits, Regeneration, Antigens, Heterophile, Neovascularization, Physiologic, Sus scrofa, Tissue Scaffolds, Adaptive Immunity, Immunity, Humoral, Hydrophobic and Hydrophilic Interactions

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