title: Development of novel combined anticalcification protocols including immunologic modification for prolonged durability of cardiac xenograft: preclinical study using large-animal long-term circulatory models.
abstract: Cardiac xenografts are conventionally cross-linked with glutaraldehyde (GA) to impart tissue stability, reduce antigenicity, and maintain tissue sterility. However, GA-fixed xenografts are prone to calcification after long-term implantation in humans, because of phospholipids, free aldehyde groups, and residual antigenicity. We evaluated preclinical safety and efficacy using large-animal long-term circulatory models for our novel combined anticalcification protocol including immunological modification, which had been proven effective in small animal experiments. Bovine/porcine xenografts were treated with decellularization, immunological modification with α-galactosidase, GA fixation with organic solvent, and detoxification with glycine. Valve conduits made of these xenografts were transplanted into the pulmonary root of goats, and hemodynamic, radiological, immunohistopathological, and biochemical results were obtained for 12 months after implantation. Evaluation of echocardiography and cardiac catheterization demonstrated good hemodynamic status and function of the pulmonary xenograft valves. Durability of the xenografts was well preserved without calcification by specimen radiography and immunohistopathological examination. The calcium concentrations of the explanted xenografts were lower than the control xenografts. This preclinical study using large-animal long-term circulatory models demonstrated that our synergistic and simultaneous employment of multiple anticalcification therapies and novel tissue treatments, including immunological modifications, have promising safety and efficacy and should be examined further in future clinical studies.
authors.affiliation: From the *Translational Xenotransplantation Research Center, Seoul National University Hospital Clinical Research Institute, Seoul, Republic of Korea; †Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Republic of Korea; and ‡Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hong-Gook
authors.initials: HG
authors.lastname: Lim
authors.forename: Saeromi
authors.initials: S
authors.lastname: Jeong
authors.forename: Jun-Seop
authors.initials: JS
authors.lastname: Shin
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D001705:Bioprosthesis / Q000009:adverse effects; D002114:Calcinosis / Q000517:prevention & control; D002417:Cattle; D024042:Collagen Type I / Q000276:immunology; D005404:Fixatives; D005976:Glutaral; D005998:Glycine; D006041:Goats; D006350:Heart Valve Prosthesis / Q000009:adverse effects; D023421:Models, Animal; D008955:Models, Cardiovascular; D034421:Sus scrofa; D023822:Tissue Engineering / Q000379:methods; D057170:Translational Research, Biomedical; D014312:Trisaccharides / Q000276:immunology; D000519:alpha-Galactosidase
chemical_list: D000910:Antibodies, Heterophile; D024042:Collagen Type I; D005404:Fixatives; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D000519:alpha-Galactosidase; D005976:Glutaral; D005998:Glycine