Philipp Jungebluth1, Evren Alici2, Silvia Baiguera3, Pontus Blomberg4, Béla Bozóky5, Claire Crowley6, Oskar Einarsson7, Tomas Gudbjartsson8, Sylvie Le Guyader9, Gert Henriksson10, Ola Hermanson11, Jan Erik Juto10, Bertil Leidner12, Tobias Lilja11, Jan Liska13, Tom Luedde14, Vanessa Lundin15, Guido Moll16, Christoph Roderburg14, Staffan Strömblad9, Tolga Sutlu2, Emma Watz17, Alexander Seifalian6, Paolo Macchiarini18. 1. Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden. 2. Cell and Gene Therapy Centre, Department of Medicine, Division of Hematology, Karolinska Institutet, Stockholm, Sweden. 3. Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. 4. Vecura, Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden. 5. Division of Pathology, Karolinska University Hospital, Stockholm, Sweden. 6. Centre for Nanotechnology and Regenerative Medicine, University College London, London, UK. 7. Department of Pulmonology, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 8. Department of Cardiothoracic Surgery, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 9. Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 10. Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden. 11. Linnaeus Center in Developmental Biology for Regenerative Medicine, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. 12. Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology (Huddinge), Karolinska University Hospital, Stockholm, Sweden. 13. Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden. 14. Department of Medicine 3, University Hospital RWTH Aachen, Aachen, Germany. 15. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. 16. Departments of Medicine and Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. 17. Departments of Medicine and Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. 18. Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden; European Airway Institute, Karolinska Institutet, Stockholm, Sweden; Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden. Electronic address: paolo.macchiarini@ki.se.
Abstract
BACKGROUND: Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. METHODS: A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 μg/kg) and epoetin beta (40,000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. FINDINGS: We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. INTERPRETATION: Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome. FUNDING: European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, StratRegen, Vinnova Foundation, Radiumhemmet, Clinigene EU Network of Excellence, Swedish Cancer Society, Centre for Biosciences (The Live Cell imaging Unit), and UCL Business.
BACKGROUND:Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. METHODS: A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 μg/kg) and epoetin beta (40,000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. FINDINGS: We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. INTERPRETATION: Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome. FUNDING: European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, StratRegen, Vinnova Foundation, Radiumhemmet, Clinigene EU Network of Excellence, Swedish Cancer Society, Centre for Biosciences (The Live Cell imaging Unit), and UCL Business.
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