Induced Remodeling of Porcine Tendons to Human Anterior Cruciate Ligaments by α-GAL Epitope Removal and Partial Cross-Linking
Open accessAbstract
This review describes a novel method developed for processing porcine tendon and other ligament implants that enables in situ remodeling into autologous ligaments in humans. The method differs from methods using extracellular matrices (ECMs) that provide postoperative orthobiological support (i.e., augmentation grafts) for healing of injured ligaments, in that the porcine bone-patellar-tendon-bone itself serves as the graft replacing ruptured anterior cruciate ligament (ACL). The method allows for gradual remodeling of porcine tendon into autologous human ACL while maintaining the biomechanical integrity. The method was first evaluated in a preclinical model of monkeys and subsequently in patients. The method overcomes detrimental effects of the natural anti-Gal antibody and harnesses anti-non-gal antibodies for the remodeling process in two steps: Step 1. Elimination of α-gal epitopes-this epitope that is abundant in pigs (as in other nonprimate mammals) binds the natural anti-Gal antibody, which is the most abundant natural antibody in humans. This interaction, which can induce fast resorption of the porcine implant, is avoided by enzymatic elimination of α-gal epitopes from the implant with recombinant α-galactosidase. Step 2. Partial cross-linking of porcine tendon with glutaraldehyde-this cross-linking generates covalent bonds in the ECM, which slow infiltration of macrophages into the implant. Anti-non-gal antibodies are produced in recipients against the multiple porcine antigenic proteins and proteoglycans because of sequence differences between human and porcine homologous proteins. Anti-non-gal antibodies bind to the implant ECM, recruit macrophages, and induce the implant destruction by directing proteolytic activity of macrophages. Partial cross-linking of the tendon ECM decreases the extent of macrophage infiltration and degradation of the implant and enables concomitant infiltration of fibroblasts that follow the infiltrating macrophages. These fibroblasts align with the implant collagen fibers and secrete their own collagen and other ECM proteins, which gradually remodel the porcine tendon into human ACL. This ligamentization process lasts ∼2 years and the biomechanical integrity of the graft is maintained throughout the whole period. These studies are the first, and so far the only, to demonstrate remodeling of porcine tendon implants into permanently functional autologous ACL in humans.
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Most homologous proteins of different species vary in some amino acid sequences.
“Most homologous proteins of different species vary in some amino acid sequences [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The section “Preclinical Studies in Monkeys > Implantation studies in monkeys” (page not supplied) says that most homologous proteins in pigs and primates have amino acid sequence differences. The claim extends that statement to different species generally, which this passage does not establish. (LLM, conf=0.84)
Experimental — accuracy not yet measuredα-gal epitopes are products of the alpha-1,3 galactosyltransferase enzyme, which has been suppressed in the common lineage of old-world monkeys, apes, and humans.
“These epitopes are products of the alpha-1,3 galactosyltransferase enzyme [116], which has been suppressed in the common lineage of these primates.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The 'Anti-Gal response in implant recipients' section (page unavailable) says α-gal epitopes are completely absent in Old World monkeys, apes, and humans. It does not state that alpha-1,3-galactosyltransferase produces the epitopes or that the enzyme was suppressed in their common lineage. The enzyme it discusses, α-galactosidase, removes epitopes from porcine tissue. (LLM, conf=0.83)
Experimental — accuracy not yet measuredECM of tissues such as heart valves, bone, tendon, and cartilage contain abundant amounts of proteoglycans (and consequently α-gal epitopes), which may remain even after a vigorous decellularization process and cause graft failure.
“Conversely, ECM of tissues such as heart valves, bone, tendon, and cartilage contain abundant amounts of proteoglycans (and consequently α-gal epitopes), which may remain even after a vigorous decellularization process and cause graft failure [47, 116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
In “Anti-Gal response in implant recipients” (page unavailable), the paper says α-gal epitopes are abundant on porcine proteoglycans and reports anti-Gal-mediated resorption of tendon and cartilage implants. It does not establish that proteoglycans and α-gal epitopes persist after vigorous decellularization across heart valves, bone, tendon, and cartilage, or that such persistence causes graft failure. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExisting amounts of α-gal epitopes in porcine SIS are presumably insufficient for activating the complement cascade.
“The existing amounts of these epitopes are presumably insufficient for activating the complement cascade.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The “Anti-Gal response in implant recipients” section says SIS has very few α-gal epitopes and that their wide spacing appears to make anti-Gal’s detrimental effects marginal. It discusses complement-mediated effects for porcine tendon implants, but does not establish that SIS epitope levels are insufficient to activate the complement cascade. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPorcine decellularized SIS mainly consists of collagen fibers, does not have many carbohydrate chains and consequently α-gals.
“Since porcine decellularized SIS mainly consists of collagen fibers, it does not have many carbohydrate chains and, consequently, α-gals.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The ‘Anti-Gal response in implant recipients’ section says SIS has a very low concentration of α-gal epitopes. It does not say SIS mainly consists of collagen fibers or has few carbohydrate chains; the collagen-fiber description in ‘Implantation of Engineered Porcine Tendons in Patients’ concerns processed tendons, not SIS. The proposed explanation for SIS’s low α-gal concentration is therefore unsupported by this copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
α-gal epitopes in porcine SIS do not alter regeneration outcomes.
“Therefore, they do not alter regeneration outcomes [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
In “Preclinical Studies in Monkeys > Anti-Gal response in implant recipients” (page unavailable), the paper reports no detrimental effect of anti-Gal on SIS implantation in monkeys or anti-Gal-producing mice, whether or not the SIS had α-gal epitopes. It does not establish that the epitopes have no effect on regeneration outcomes; it describes their detrimental effects in SIS as seemingly marginal. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe resulting ACLs performed optimal function through 10 years of follow-up.
“Successful conversion of xenografts to humanized ACLs occurred in five out of six patients over two years, and the resulting ACLs performed their optimal function through 10 years of follow-up [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The “Implantation of Engineered Porcine Tendons in Patients” section reports that the implants in five evaluable patients continued to function as autologous ACLs for more than 10 years. It does not establish that their function was optimal throughout that period; the stated success criteria were assessed at 24 months. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn six patients with injured ACL, α-galactosidase-treated porcine tendons modulated transplant immunogenicity.
“Stone et al. utilized α-galactosidase treated porcine tendons to reconstruct injured anterior cruciate ligaments (ACL) of six patients. They observed the efficacy of enzymatic treatment in modulating the transplants’ immunogenicity.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
The “Implantation of Engineered Porcine Tendons in Patients” section reports that α-galactosidase-treated porcine tendons were implanted for ruptured ACLs and describes a limited anti-Gal antibody response. However, the trial enrolled 10 patients; six were evaluable at 24 months, not the total number who received implants. The paper also describes partially cross-linking the tendons, so it does not isolate the effect of enzymatic treatment alone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAll mammals except old-world monkeys, apes, and humans express α-gal epitopes on their proteoglycans, glycoproteins, and glycolipids.
“All mammals except old-world monkeys, apes, and humans express α-gal epitopes on their proteoglycans, glycoproteins, and glycolipids.”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
α-gal epitopes are identified as one of the main barriers to the clinical application of processed animal bone grafts and tendons.
“Nonetheless, α-gal epitopes are identified as one of the main barriers to the clinical application of processed animal bone grafts [124] and tendons [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
Successful conversion of xenografts to humanized ACLs occurred in five out of six patients over two years.
“Successful conversion of xenografts to humanized ACLs occurred in five out of six patients over two years, and the resulting ACLs performed their optimal function through 10 years of follow-up [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
In a clinical trial, α-gal depleted porcine tendons partially crosslinked with low concentration GA (0.1%) and detoxified with glycine solution were successfully remodeled in patients, exhibiting immune response equilibrium and allowing fibroblast alignment.
“In the previously discussed clinical trial, α-gal depleted porcine tendons, which were partially crosslinked with a low concentration of GA (0.1%) and detoxified with glycine solution, were successfully remodeled in patients. The porcine tendons exhibited an immune response equilibrium, allowing fibroblast alignment [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
Following implantation of xenografts, α-gal antibodies peak within two weeks, while anti-non-gal antibodies require one to six months.
“Following implantation of xenografts, α-gal antibodies peak within two weeks, while anti-non-gal antibodies require one [47] to six months [116].”
From Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine (2023) · cites this paper as [116]
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Healthy but not osteoarthritic human meniscus-derived matrix scaffolds promote meniscus repair
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Biomechanical Analysis of Silk as a Tendon or Ligament Replacement
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Anti-Gal and Anti-non Gal Antibodies in Regeneration of Extracellular Matrix Bio-Implants
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Human corneal decellularization for regenerative therapy from methods to clinical applications
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- Authors
- Stone, K. R., Walgenbach, A., & Galili, U.
- Affiliations
- Stone Clinic (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Galili, Uri
- Venue
- Tissue Engineering Part B: Reviews
- Publisher
- SAGE Publications
- Published
- 2017-08
- Volume
- 23
- Issue
- 4
- Pages
- 412-419
- ISSN
- 1937-3368 (ISSN-L)
- 1937-3376
- PMC
- PMC5567590
- OpenAlex
- W2590437864
- Cited by
- 22
- References
- 54
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 4 · 2018: 2 · 2017: 1
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Tissue Engineering Part B Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Tendon Structure and Treatment
- Keywords
- anterior cruciate ligament reconstruction, xenotransplantation, glutaraldehyde crosslinking, macrophage infiltration, implant resorption, fibroblast infiltration, bone-patellar tendon-bone graft
- MeSH terms
- Animals, Antibodies, Epitopes, Extracellular Matrix, Humans, Swine, Tendons, Anterior Cruciate Ligament
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