Graft-specific immune tolerance is determined by residual antigenicity of xenogeneic extracellular matrix scaffolds
Open accessAbstract
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.
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Retention of chemicals such as SDS has been reported to promote inflammation and foreign body reactions.
“Moreover, retention of chemicals such as SDS has been reported to promote inflammation and foreign body reactions [92,186].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [186]
The Discussion reports that SDS can damage ECM proteins, harm repopulating cells, and stimulate an innate immune-mediated foreign body response. It does not establish that retention of SDS in a scaffold, rather than damage caused by its use, promotes that response. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSulfobetaines have been successfully exploited in solubilization, the process of removing hydrophobic and hydrophilic immunogenic content of tissues/organs.
“Nevertheless, relying on the dual structure of zwitterionic detergents, sulfobetaines have been successfully exploited in solubilization, the process of removing hydrophobic and hydrophilic immunogenic content of tissues/organs [88].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Results and Discussion report that selected sulfobetaines helped remove lipophilic antigens from bovine pericardium, and the treatment also removed hydrophilic antigens. However, Materials and methods describes a separate hydrophile-solubilizing step before sulfobetaine treatment, and the Discussion says sulfobetaines did not significantly increase hydrophilic antigen removal compared with no detergent. The study concerns bovine pericardial tissue, not organs generally; page numbers were unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRetention of SDS within decellularized tissues promotes inflammation and FBR following implantation.
“However, retention of SDS within decellularized tissues promotes inflammation and FBR following implantation.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Discussion (page unavailable) says SDS can denature ECM proteins and be toxic to repopulating cells, stimulating an innate immune-mediated foreign body response. It also links SDS-related ECM damage to fibrous encapsulation after implantation. It does not establish that SDS retained within decellularized tissue is what causes the inflammation or response. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCytotoxic effects of remaining SDS for recellularization and regeneration partially explain the inflammatory/FBR reaction to retained SDS.
“This reaction is partially explained by the cytotoxic effects of remaining SDS for the recellularization and regeneration process [88, 89].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Discussion states that SDS can be toxic to repopulating cells and stimulate an innate immune-mediated foreign body response. It does not specifically identify retained SDS as the cause or establish its effect on regeneration, so the claim is more specific than the passage supports (Discussion; page not available in our copy). (LLM, conf=0.84)
Experimental — accuracy not yet measuredSulfobetaines are a subgroup of zwitterionic detergents with good efficacy in solubilizing proteins and negligible compromise on ECM ultrastructure.
“Sulfobetaines are a subgroup of zwitterionic detergents with good efficacy in solubilizing proteins and negligible compromise on ECM ultrastructure.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Discussion describes sulfobetaines as zwitterionic detergents and powerful protein solubilizers. The Results section, “Antigen removal with sulfobetaines preserves native extracellular matrix Structure, composition and function” (page not provided), reports broadly maintained ECM morphology, but also less clearly defined collagen bundles and disrupted basement-membrane components with ASB-14. Thus, negligible compromise to ECM structure is too broad for the sulfobetaines studied. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Sulfobetaines have relatively higher potency in extracting hydrophobic antigens than ionic detergents and seem to be the most effective agent in eliminating hydrophobic xenoantigens.
“They have relatively higher potency in extracting hydrophobic antigens than ionic detergents and seem to be the most effective agent in eliminating hydrophobic xenoantigens [88].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Discussion (page unavailable) describes poor removal of lipophilic antigens by ionic detergents such as SDS, while the Introduction calls sulfobetaines particularly promising for removing them. But the Discussion also says not all sulfobetaines tested reduced lipophilic antigenicity, and the Results identify ASB-14 and ASB-16—not sulfobetaines generally—as the most effective compounds tested. The paper therefore supports the comparison but not the unqualified claim that sulfobetaines are the most effective agent. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAmidosulfobetaine-16 treatment produced bioprosthetic heart valves with desired remodeling and comparable immunogenicity to glutaraldehyde-crosslinked valves.
“It produced bioprosthetic heart valves with the desired remodeling and comparable immunogenicity to glutaraldehyde (GA) crosslinked valves which have previously been shown to prevail over adaptive immunity [88].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
The Results report that ASB-16 3% scaffolds had a humoral immune response not significantly different from glutaraldehyde-fixed bovine pericardium, and the Discussion describes constructive remodeling. But the study tested scaffolds, not finished heart valves; it also found less cell-mediated immune infiltration with ASB-16 than with glutaraldehyde-fixed scaffolds. The Introduction says glutaraldehyde fixation incompletely masks antigenicity, contrary to the suggestion that those valves overcome adaptive immunity. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredECM denaturation by ionic detergents may alter composition, mechanical features, and morphology to impede regenerative processes and provoke adverse immune reactions and FBR.
“This ECM denaturation may alter the composition, mechanical features, and morphology to impede regenerative processes and provoke adverse immune reactions and FBR [88].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
In a preclinical study, amidosulfobetaine-16 (3% w/v) successfully removed 92% of total hydrophobic antigens (99% reduction in both α-gal and MHC I) in bovine pericardium.
“In a preclinical study, amidosulfobetaine-16 (3% w/v) successfully removed 92% of total hydrophobic antigens (99% reduction in both α-gal and MHC I) in the bovine pericardium.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [88]
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Optimization of a high-throughput shotgun immunoproteomics pipeline for antigen identification
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Antigen Removal Approach to Murine Larynx Engineering Optimizes Extracellular Matrix Preservation
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- Authors
- Dalgliesh, A. J., Parvizi, M., Lopera-Higuita, M., Shklover, J., & Griffiths, L. G.
- Affiliations
- Mayo Clinic (US)
- University of California, Davis (US)
- Corresponding author
- Griffiths, Leigh G.
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 79
- Pages
- 253-264
- ISSN
- 1742-7061 (ISSN-L)
- PMC
- PMC6349227
- OpenAlex
- W2887022196
- Cited by
- 57
- References
- 49
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 13 · 2020: 5 · 2019: 9
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Biomaterialia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (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
- antigen removal, innate immune tolerance, decellularization, tissue engineering biomaterials, protein organization
- MeSH terms
- Animals, Antigens, Betaine, Cattle, Collagen, Extracellular Matrix, Humans, Immune Tolerance, Lipids, Pericardium, Tissue Scaffolds, Adaptive Immunity, Immunity, Humoral, Heterografts
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