Ice-free Cryopreserved Heart Valves: A Novel Decellularization and Heart Valve Replacement Method for Pediatrics?
Anna C. Biermann1, Julia Marzi2, Julian L. Wichmann3, Eike Nagel4, Kelvin GM Brockbank5, Katja Schenke-Layland6, Ulrich A. Stock1.
1Department of Cardiothoracic Surgery, Royal Brompton and Harefield Foundation Trust, Harefield, United Kingdom, 2Department of Women's Health, Research Institute for Women's Health, Eberhard-Karls-University, Tuebingen, Germany, 3University Hospital Frankfurt Goethe University, Frankfurt am Main, Germany, 4Department of Diagnostics and Interventional Radiology, University Hospital Frankfurt Goethe University, Frankfurt am Main, Germany, 5The Georgia Tech/Emory Center for the Engineering of Living Tissues, Georgia Institute of Technology, Atlanta, GA, USA, 6Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Department of Cell and Tissue Engineering, Stuttgart, Germany.
Allogeneic frozen cryopreserved (FC) heart valves are the current gold standard for heart valve replacement involving reconstruction of the right ventricular outflow tract . Immune responses, inflammation and structural deterioration limit their long-term function especially for pediatrics. In contrast, ice-free cryopreserved (IFC) valves in allogeneic mid-term large animal studies demonstrated superior performance, better matrix preservation and decreased immunological response. In this study the pathobiology of early events and long-term performance of IFC pulmonary allografts in a sheep model were assessed.
IFC and FC allografts were transplanted in 12 juvenile sheep for 12 months and 6 IFC allografts were transplanted for 1, 2, 3, 4, 8, and 12 weeks. Computed tomography (CT), cardiac magnetic resonance imaging (MRI) and 2D-echocardiography were performed for functional testing. Histology, multiphoton autofluorescence imaging and for the first time Raman microspectroscopy were performed to evaluate the explants with a focus on matrix integrity.
Excellent hemodynamic properties were detected after 12 months of implantation of IFC valves. IFC leaflets were acellular after one week and remained acellular for 12 month, whereas 50% (3/6) of the long-term FC explants showed inflamed, thickened and moderately infiltrated leaflets with predominately CD3 positive T lymphocytes. Both qualitative and quantitative assessment of the matrix integrity revealed native like collagen structures in the IFC leaflets early after implantation and 12 months after explantation, whereas clear structural remodeling was observed in the FC treated tissues.
IFC treated valves have the ability to overcome known limitations of conventional frozen cryopreserved allograft due to their good hemodynamic function, reduced immunological reactions and native like matrix structures after 12 months of implantation and present a promising alternative for pediatric patients. The immediate acellularity of the leaflets indicates that IFC can be utilized as a novel decellularization method with optimal native matrix preservation.
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