Tissue Engineered Valves

Objectives

Our long term goals are to achieve off the shelf availability of non- immunogenic heart valve prosthesis based on modified xenogenic (porcine) decellularized heart valve matrices.

Our short term goals are to provide non-immunogenic heart valve prosthesis based on modified xenogenic (porcine) decellularized heart valve matrices ready to be clinically tested in a trial in the near future.

Milestones: 

  • Removal/Reduction of xenogens on porcine natural heart valve matrices by modification of decellularization protocols and enzymatic treatment of the glycocalix
  • Generation of low reactive heart valve matrices in “humanized” alpha-GalT ko pig models
  • Functionality tests of low/non-immunogenic natural heart valve matrices in large animal experiments (sheep/pig/non human primate)

Objectives

Heart valve replacement is a life-saving procedere conducted worldwide approximately 300.000 times per year. Mechanical devices and bioprosthetic valves, made out of fixed animal tissue, are used, but with severe side effects. Lifelong anticoagulation for mechanical valves and restricted durability of 5-15 years for bioprosthetic valves limit the application and reduce the prognosis of the patients. Furthermore, in pediatric patients implanted valves have to be replaced within years due to the growth of the child and accelerated degradation of the implant.

Thus, an optimal heart valve substitute would require an unlimited durability, the capacity to grow and would not require lifelong anticoagulation. All these specifications seem to be fulfilled by decellularized heart valve allografts, which were successfully developed and implanted in our clinical department. These valves display a human biological matrix that is revitalized by recipient cells in vivo forming a functional endothelium and living interstitium.

One major drawback that prevents this technology to become applicable for the huge existing patient cohort, is the limited availability. At the moment, only human derived matrices can be used. Early clinical trials and animal experiments in sheep showed porcine derived matrices to fail due to acute or chronic rejection, in men caused by xenoantigens like the alpha-Gal epitope.

The aim of this project is, therefore, to develop a porcine derived decellularized matrix that is well tolerated in humans. To reduce its immunogenicity, modification of the current decellularization protocol towards optimized removal of xenoantigens will be combined with enzymatic treatment to specifically remove known xenoantigens. These will include the alpha-Gal epitope, but also yet unidentified xenoantigens reacting with human natural occurring pig antibodies. With the help of animal models as sheep and non-human primates as test systems for antigenicity, and mechanical and biological functionality but also as genetically altered pigs i.e. alpha-1,3GT k.o that may serve as valve donors for modifications, the generation of clinically applicable xenogenic non-immunogenic natural heart valve matrix for heart valve replacement will be addressed.

Collaborations

  • D. Hilfiker-Kleiner, REBIRTH Unit Endogenous Regeneration Mechanisms of the Heart: Endogenous Regeneration
  • S. Cebotari, REBIRTH Unit Large Animal Models for Myocardial Repair: Functional tests in large animal models
  • H. Niemann, REBIRTH Unit Large Animal Models: Transgenic / cloned / chimeric pigs
  • W. Wolkers, REBIRTH Unit Biostabilization of Tissues and Macromolecular Assemblies: Freeze drying of matrices
  • F. Büttner, REBIRTH Unit Stem Cell Glycomics and Proteomics: Identification of immunogenic glyco-epitopes on xenogeneic heart valves.
  • S. Korossis, REBIRTH Unit Biohybrid Lung: Biomechanical testing of matrices.
  • M. Scherr, Dept. of Hematology and Oncology, MHH: Cell labeling with viral vectors.
  • G. Brandes, Laboratory for Cell Biology and Electron Microscopy, MHH: SEM
  • R. Schwinzer., Dept. of Visceral and Transplantation Surgery, MHH: Xenotransplantation
  • Corelife GbR, Hannover: Cardiovascular TE

Publications

2013 - ongoing

2018

Manikowski D, Andrée B, Samper E, Saint-Marc C, Olmer R, Vogt P, Strauß S, Haverich A, Hilfiker A. Human adipose tissue-derived stromal cells in combination with exogenous stimuli facilitate three-dimensional network formation of human endothelial cells derived from various sources. Vascular Pharmacology. 2018.

Iablonskii P, Cebotari S, Ciubotaru A, Sarikouch S, Hoeffler K, Hilfiker A, Haverich A, Tudorache I. Decellularized mitral valve in a long-term sheep model†. European Journal of Cardio-Thoracic Surgery. 2018:ezx485-ezx.

Vasquez-Rivera A, Sommer KK, Oldenhof H, Higgins AZ, Brockbank KGM, Hilfiker A, Wolkers WF. Simultaneous monitoring of different vitrification solution components permeating into tissues. Analyst. 2018;143(2):420-8.

2017

Theodoridis K, Tudorache I, Cebotari S, Calistru A, Meyer T, Sarikouch S, Bara C, Haverich A, Hilfiker A. (*) Six-Year-Old Sheep as a Clinically Relevant Large Animal Model for Aortic Valve Replacement Using Tissue-Engineered Grafts Based on Decellularized Allogenic Matrix. Tissue Eng Part C Methods. 2017;23(12):953-63.

Mogaldea A, Goecke T, Theodoridis K, Haverich A, Cebotari S, Hilfiker A. Tissue Engineering of Vein Valves Based on Decellularized Natural Matrices. Cells Tissues Organs. 2017;204(3-4):199-209.

Kolster M, Wilhelmi M, Schrimpf C, Hilfiker A, Haverich A, Aper T. Outgrowing endothelial and smooth muscle cells for tissue engineering approaches. Journal of Tissue Engineering. 2017;8:2041731417698852.

Granados M, Morticelli L, Andriopoulou S, Kalozoumis P, Pflaum M, Iablonskii P, Glasmacher B, Harder M, Hegermann J, Wrede C, Tudorache I, Cebotari S, Hilfiker A, Haverich A, Korossis S. Development and Characterization of a Porcine Mitral Valve Scaffold for Tissue Engineering. Journal of Cardiovascular Translational Research. 2017;10(4):374-90.

Goecke T, Theodoridis K, Tudorache I, Ciubotaru A, Cebotari S, Ramm R, Hoffler K, Sarikouch S, Vasquez-Rivera A, Haverich A, Wolkers WF, Hilfiker A. In vivo performance of freeze-dried decellularized pulmonary heart valve allo- and xenografts orthotopically implanted into juvenile sheep. Acta Biomater. 2017/12/02 ed2017.

Theodoridis K, Tudorache I, Cebotari S, Calistru A, Meyer T, Sarikouch S, Bara C, Haverich A, Hilfiker A. Six-Year-Old Sheep as a Clinically Relevant Large Animal Model for Aortic Valve Replacement Using Tissue-Engineered Grafts Based on Decellularized Allogenic Matrix. Tissue Eng Part C Methods. 2017/09/20 ed2017.

Braniste T, Tiginyanu I, Horvath T, Raevschi S, Andree B, Cebotari S, Boyle EC, Haverich A, Hilfiker A. Targeting Endothelial Cells with Multifunctional GaN/Fe Nanoparticles. Nanoscale Res Lett. 2017/08/12 ed2017. p. 486.

Granados M, Morticelli L, Andriopoulou S, Kalozoumis P, Pflaum M, Iablonskii P, Glasmacher B, Harder M, Hegermann J, Wrede C, Tudorache I, Cebotari S, Hilfiker A, Haverich A, Korossis S. Development and Characterization of a Porcine Mitral Valve Scaffold for Tissue Engineering. J Cardiovasc Transl Res. 2017/05/04 ed2017. p. 374-90.

2016

Braniste T, Tiginyanu I, Horvath T, Raevschi S, Cebotari S, Lux M, Haverich A, Hilfiker A. Viability and proliferation of endothelial cells upon exposure to GaN nanoparticles. Beilstein Journal of Nanotechnology. 2016;7:1330-7.

Lux M, Andrée B, Horvath T, Nosko A, Manikowski D, Hilfiker-Kleiner D, Haverich A, Hilfiker A. In vitro maturation of large-scale cardiac patches based on a perfusable starter matrix by cyclic mechanical stimulation. Acta Biomaterialia. 2016;30:177-87.

Tudorache I, Theodoridis K, Baraki H, Sarikouch S, Bara C, Meyer T, Hoffler K, Hartung D, Hilfiker A, Haverich A, Cebotari S. Decellularized aortic allografts versus pulmonary autografts for aortic valve replacement in the growing sheep model: haemodynamic and morphological results at 20 months after implantation. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2016;49(4):1228-38.

Theodoridis K, Muller J, Ramm R, Findeisen K, Andree B, Korossis S, Haverich A, Hilfiker A. Effects of combined cryopreservation and decellularization on the biomechanical, structural and biochemical properties of porcine pulmonary heart valves. Acta biomaterialia. 2016;43:71-7.

Ramm R, Niemann H, Petersen B, Haverich A, Hilfiker A. Decellularized GGTA1-KO pig heart valves do not bind preformed human xenoantibodies. Basic research in cardiology. 2016;111(4):39.

Aper T, Wilhelmi M, Gebhardt C, Hoeffler K, Benecke N, Hilfiker A, Haverich A. Novel method for the generation of tissue-engineered vascular grafts based on a highly compacted fibrin matrix. Acta biomaterialia. 2016;29:21-32.

2015

Wolkers WF, Hilfiker A. Freeze-Drying of Decellularized Heart Valve Tissues. Methods Mol Biol. 2015;1257:499-506.

Wang S, Oldenhof H, Goecke T, Ramm R, Harder M, Haverich A, Hilfiker A, Wolkers WF. Sucrose Diffusion in Decellularized Heart Valves for Freeze-Drying. Tissue Eng Part C Methods. 2015;21(9):922-31.

Tudorache I, Theodoridis K, Baraki H, Sarikouch S, Bara C, Meyer T, Hoffler K, Hartung D, Hilfiker A, Haverich A, Cebotari S. Decellularized Aortic Allografts Versus Pulmonary Autografts for Aortic Valve Replacement in the Growing Sheep Model: Haemodynamic and Morphological Results at 20 Months after Implantation. Eur J Cardiothorac Surg. 2015.

Theodoridis K, Tudorache I, Calistru A, Cebotari S, Meyer T, Sarikouch S, Bara C, Brehm R, Haverich A, Hilfiker A. Successful Matrix Guided Tissue Regeneration of Decellularized Pulmonary Heart Valve Allografts in Elderly Sheep. Biomaterials. 2015;52:221-8.

Ramm R, Hartmann T, Tudorache I, Haverich A, Hilfiker A. No Evidence for Alphagal Epitope Transfer from Media Containing Fcs onto Human Endothelial Cells in Culture. Xenotransplantation. 2015;22(5):345-55.

Lux M, Andree B, Horvath T, Nosko A, Manikowski D, Hilfiker-Kleiner D, Haverich A, Hilfiker A. In Vitro Maturation of Large-Scale Cardiac Patches Based on a Perfusable Starter Matrix by Cyclic Mechanical Stimulation. Acta Biomater. 2015.

Iablonskii P, Cebotari S, Tudorache I, Granados M, Morticelli L, Goecke T, Klein N, Korossis S, Hilfiker A, Haverich A. Tissue-Engineered Mitral Valve: Morphology and Biomechanics Dagger. Interact Cardiovasc Thorac Surg. 2015;20(6):712-9; discussion 9.

Hofmann AD, Hilfiker A, Haverich A, Andree B, Kuebler J, Ure B. Biovam in the Rat Model: A New Approach of Vascularized 3d Tissue for Esophageal Replacement. Eur J Pediatr Surg. 2015;25(2):181-8.

Goecke T, Tudorache I, Hilfiker A, Haverich A, Cebotari S. [Prefabrication of Heart Valves]. Chirurg. 2015;86(3):251-3. Prafabrikation von Herzklappen.

Goecke T, Hilfiker A, Haverich A, Cebotari S. Investigation of Inflammatory Response of Decellularized Porcine Aortic Tissue in Mice: Can We Rely on This Experimental Setting? Eur J Cardiothorac Surg. 2015;47(3):e90-1. Epub 2014/12/30.

Aper T, Wilhelmi M, Gebhardt C, Hoeffler K, Benecke N, Hilfiker A, Haverich A. Novel Method for the Generation of Tissue-Engineered Vascular Grafts Based on a Highly Compacted Fibrin Matrix. Acta Biomater. 2015.

2014

Wang S, Oldenhof H, Dai X, Haverich A, Hilfiker A, Harder M, Wolkers WF. Protein Stability in Stored Decellularized Heart Valve Scaffolds and Diffusion Kinetics of Protective Molecules. Biochim Biophys Acta. 2014;1844(2):430-8.

Vukadinovic-Nikolic Z, Andree B, Dorfman SE, Pflaum M, Horvath T, Lux M, Venturini L, Bar A, Kensah G, Lara AR, Tudorache I, Cebotari S, Hilfiker-Kleiner D, Haverich A, Hilfiker A. Generation of Bioartificial Heart Tissue by Combining a Three-Dimensional Gel-Based Cardiac Construct with Decellularized Small Intestinal Submucosa. Tissue Engineering Part A. 2014;20(3-4):799-809.

Minol JP, Baraki H, Akhyari P, Bagaev E, Suprunov M, Brandes G, Bara C, Hort W, Hurschler C, Sigler M, Haverich A, Hilfiker A, Lichtenberg A. Tracheal Cartilage - Evaluating the Potential of a Novel Biomaterial for Reconstructive Cardiovascular Procedures. J Tissue Eng Regen Med. 2014;8(11):850-61.

Melk A, Tegtbur U, Hilfiker-Kleiner D, Eberhard J, Saretzki G, Eulert C, Kerling A, Nelius AK, Homme M, Strunk D, Berliner D, Rontgen P, Kuck M, Bauersachs J, Hilfiker A, Haverich A, Bara C, Stiesch M. Improvement of Biological Age by Physical Activity. International Journal of Cardiology. 2014;176(3):1187-9.

Hochberger J, Koehler P, Wedi E, Gluer S, Rothstein RI, Niemann H, Hilfiker A, Gonzalez S, Kruse E. Transplantation of Mucosa from Stomach to Esophagus to Prevent Stricture after Circumferential Endoscopic Submucosal Dissection of Early Squamous Cell. Gastroenterology. 2014;146(4):906-9.

Eberhard J, Stiesch M, Kerling A, Bara C, Eulert C, Hilfiker-Kleiner D, Hilfiker A, Budde E, Bauersachs J, Kuck M, Haverich A, Melk A, Tegtbur U. Moderate and Severe Periodontitis Are Independent Risk Factors Associated with Low Cardiorespiratory Fitness in Sedentary Non-Smoking Men Aged between 45 and 65 Years. J Clin Periodontol. 2014;41(1):31-7.

Andree B, Bela K, Horvath T, Lux M, Ramm R, Venturini L, Ciubotaru A, Zweigerdt R, Haverich A, Hilfiker A. Successful Re-Endothelialization of a Perfusable Biological Vascularized Matrix (Biovam) for the Generation of 3d Artificial Cardiac Tissue. Basic Res Cardiol. 2014;109(6):441.

2013

Westhoff-Bleck M, Podewski E, Hilfiker A, Hilfiker-Kleiner D. Cardiovascular Disorders in Pregnancy: Diagnosis and Management. Best Practice & Research Clinical Obstetrics & Gynaecology. 2013;27(6):821-34.

Tudorache I, Calistru A, Baraki H, Meyer T, Hoffler K, Sarikouch S, Bara C, Gorler A, Hartung D, Hilfiker A, Haverich A, Cebotari S. Orthotopic Replacement of Aortic Heart Valves with Tissue-Engineered Grafts. Tissue Eng Part A. 2013;19(15-16):1686-94.

Steele TW, Huang CL, Nguyen E, Sarig U, Kumar S, Widjaja E, Loo JS, Machluf M, Boey F, Vukadinovic Z, Hilfiker A, Venkatraman SS. Collagen-Cellulose Composite Thin Films That Mimic Soft-Tissue and Allow Stem-Cell Orientation. J Mater Sci Mater Med. 2013;24(8):2013-27.

Schilling T, Brandes G, Tudorache I, Cebotari S, Hilfiker A, Meyer T, Biskup C, Bauer M, Waldmann KH, Bach FW, Haverich A, Hassel T. In Vivo Degradation of Magnesium Alloy La63 Scaffolds for Temporary Stabilization of Biological Myocardial Grafts in a Swine Model. Biomed Tech (Berl). 2013;58(5):407-16.

Derks M, Sturm T, Haverich A, Hilfiker A. Isolation and Chondrogenic Differentiation of Porcine Perichondrial Progenitor Cells for the Purpose of Cartilage Tissue Engineering. Cells Tissues Organs. 2013;198(3):179-89.

Ciubotaru A, Cebotari S, Tudorache I, Beckmann E, Hilfiker A, Haverich A. Biological Heart Valves. Biomed Tech (Berl). 2013;58(5):389-97.

Aper T, Teebken OE, Kruger A, Heisterkamp A, Hilfiker A, Haverich A. Development of Implantable Autologous Small-Calibre Vascular Grafts from Peripheral Blood Samples. Zentralbl Chir. 2013;138(2):173-9.

Andree B, Bar A, Haverich A, Hilfiker A. Small Intestinal Submucosa Segments as Matrix for Tissue Engineering: Review. Tissue Eng Part B Rev. 2013;19(4):279-91.

2006 - 2012

2012

Wang S, Goecke T, Meixner C, Haverich A, Hilfiker A, Wolkers WF. Freeze-Dried Heart Valve Scaffolds. Tissue Eng Part C Methods. 2012;18(7):517-25.

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