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.
The European Commission (FP7 EU Project: 280584-2BIOtracheaCP-FPFP7-NMP-2011-SMALL-5), the Knut and Alice Wallenberg Foundation, Swedish Research Council, and the StratRegen funded preclinical and postoperative in-vitro studies, gene expression, cell characterisation, and imaging. The Vinnova Foundation, Radiumhemmet, and Clinigene EU Network of Excellence funded multiplex and flow cytometric analyses. The Swedish Cancer Society supported the epigenetic studies. The Centre for Biosciences, the Knut and Alice Wallenberg Foundation, and the Swedish Research Council supported the Live Cell imaging Unit at the Department of Biosciences and Nutrition, Karolinska Institutet, used for live cell imaging. ERC-2007-Stg/208237-Luedde-Med3-Aachen funded the miRNA studies. The UCL Business supported the development of the three-dimensional nanocomposite scaffold. We thank all the health professionals of the Karolinska University Hospital in Huddinge, Stockholm, Sweden, without whom the transplantation could not have been done; Harvard Apparatus (Hollison, MA, USA) and Hugo Sachs Elektronik-Harvard Apparatus GmbH (March-Hugstetten, Germany) for supporting us with the bioreactor and the supervision of its use; Peter Güntner, for image analysis and measurements for scaffold production, and Anders Svensson, for three-dimensional volume image rendering, both from the Department of Radiology, Karolinska University Hospital Huddinge, Stockholm, Sweden; all the staff of the Landspitali University Hospital in Reykjavik, for the excellent support with the preoperative and postoperative care of the patient; Alessandra Bianco and Costantino Del Gaudio from Department of Science and Chemical Technologies, Intrauniversitary Consortium for Material Science Technology (INSTM), Research Unit Tor Vergata, Rome, Italy, for bi-dimensional and three-dimensional mathematical model for tracheal lateral area assessment; Iyadh Douagi from the Center of Hematology and Regenerative Medicine, Department of Medicine, Karolinska Insitutet for his assistance with flow cytometry; and Ulrika Felldin from ACTREM, Karolinska Institutet for her assistance with cell isolation.