title: Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden.
authors: Philipp
authors: P
authors: Jungebluth
authors: Cell and Gene Therapy Centre, Department of Medicine, Division of Hematology, Karolinska Institutet, Stockholm, Sweden.
authors: Evren
authors: E
authors: Alici
authors: Advanced Center for Translational Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Silvia
authors: S
authors: Baiguera
authors: Vecura, Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden.
authors: Pontus
authors: P
authors: Blomberg
authors: Division of Pathology, Karolinska University Hospital, Stockholm, Sweden.
authors: Béla
authors: B
authors: Bozóky
authors: Centre for Nanotechnology and Regenerative Medicine, University College London, London, UK.
authors: Claire
authors: C
authors: Crowley
authors: Department of Pulmonology, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Oskar
authors: O
authors: Einarsson
authors: Department of Cardiothoracic Surgery, Landspitali University Hospital, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Tomas
authors: T
authors: Gudbjartsson
authors: Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors: Sylvie
authors: S
authors: Le Guyader
authors: Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden.
authors: Gert
authors: G
authors: Henriksson
authors: Linnaeus Center in Developmental Biology for Regenerative Medicine, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Ola
authors: O
authors: Hermanson
authors: Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden.
authors: Jan Erik
authors: JE
authors: Juto
authors: Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology (Huddinge), Karolinska University Hospital, Stockholm, Sweden.
authors: Bertil
authors: B
authors: Leidner
authors: Linnaeus Center in Developmental Biology for Regenerative Medicine, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Tobias
authors: T
authors: Lilja
authors: Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors: Jan
authors: J
authors: Liska
authors: Department of Medicine 3, University Hospital RWTH Aachen, Aachen, Germany.
authors: Tom
authors: T
authors: Luedde
authors: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Vanessa
authors: V
authors: Lundin
authors: Departments of Medicine and Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Guido
authors: G
authors: Moll
authors: Department of Medicine 3, University Hospital RWTH Aachen, Aachen, Germany.
authors: Christoph
authors: C
authors: Roderburg
authors: Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors: Staffan
authors: S
authors: Strömblad
authors: Cell and Gene Therapy Centre, Department of Medicine, Division of Hematology, Karolinska Institutet, Stockholm, Sweden.
authors: Tolga
authors: T
authors: Sutlu
authors: Departments of Medicine and Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors: Emma
authors: E
authors: Watz
authors: Centre for Nanotechnology and Regenerative Medicine, University College London, London, UK.
authors: Alexander
authors: A
authors: Seifalian
authors: 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.
authors: Paolo
authors: P
authors: Macchiarini
mesh_terms: D000328:Adult; D019149:Bioreactors; D001807:Blood Vessel Prosthesis; D016026:Bone Marrow Transplantation; D001984:Bronchial Neoplasms / Q000601:surgery*; D001999:Bronchoscopy; D018277:Carcinoma, Mucoepidermoid / Q000601:surgery; D049109:Cell Proliferation; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D053761:Nanocomposites / Q000737:chemistry; D009364:Neoplasm Recurrence, Local / Q000601:surgery; D018919:Neovascularization, Physiologic; D011093:Polyethylene Terephthalates; D011994:Recombinant Proteins / Q000627:therapeutic use; D012038:Regeneration; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D014134:Tracheal Neoplasms / Q000601:surgery*; D014182:Transplantation, Autologous
chemical_list: C505362:MIRN16 microRNA, human; C522425:MIRN34 microRNA, human; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D011093:Polyethylene Terephthalates; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D000068817:Epoetin Alfa