In Vivo Tissue Engineering of Human Airways

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Volume 75, Issue 1, Pages (January 2010)

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Presentation transcript:

In Vivo Tissue Engineering of Human Airways Emmanuel Martinod, MD, PhD, Joseph Paquet, PhD, Hervé Dutau, MD, PhD, Dana M. Radu, MD, Morad Bensidhoum, PhD, Sébastien Abad, MD, PhD, Yurdagül Uzunhan, MD, PhD, Eric Vicaut, MD, PhD, Hervé Petite, PhD The Annals of Thoracic Surgery Volume 103, Issue 5, Pages 1631-1640 (May 2017) DOI: 10.1016/j.athoracsur.2016.11.027 Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 The innovative surgical procedure performed in the 2 patients. (A) Under general anesthesia, ventilation was maintained using a cross-field endotracheal tube inserted into the tracheostomy stoma. (B) The anterior wall of the cricoid cartilage and the upper trachea were fully resected preserving the posterior membrane (PM) to prevent injury to the recurrent laryngeal nerves (RLN). Cartilage rings were fully removed. (C) A custom-made, fully covered nitinol stent (Silmet; Novatech, La Ciotat, France) was inserted into the airways to avoid airway collapse (S). Both ends of the stent were fixed using nonabsorbable sutures to prevent migration. (D) A human leukocyte antigen-ABO gender-mismatched –80°C cryopreserved aortic allograft (CAA) from a certified tissue bank was removed from dry ice and thawed by keeping the container bags at room temperature for 10 minutes, followed by 10 minutes in a 37°C water bath. The bags were opened, and the graft was washed in a sterile saline solution for 5 minutes. The CAA was prepared and sutured using absorbable sutures. (E) The CAA was protected by a sterno-omo-thyrohyoid muscle flap to provide neovascularization and avoid fistulization to surrounding structures. (F) The skin was closed on a temporary tracheostomy tube, allowing the patient to breathe and speak normally by the natural airways when occluded. The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Regeneration of calcified cartilage within the implanted aortic matrix (white arrows) in patient 2 is shown on computed tomography scan (A) coronal, (B) sagittal, and (C and D) transverse planes. Calcification was only observed within the aortic graft and preserved the remaining posterior tracheal membrane. The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Endoscopic evaluation shows regenerated tracheas at long-term follow-up using (A) virtual three-dimensional bronchoscopy in patient 1 and (B) conventional bronchoscopy in patient 2. Regenerated cartilage rings (★) were strong enough to support the rigidity of airway lumen after stent removal. The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Biological studies of regenerated tracheas and implanted aortic matrices. (A) Pathologic examination of graft biopsy specimens (hematoxylin-eosin-safron stain at original magnification ×50) shows a regenerated continuous mixed epithelium (*) associated with some clusters of regenerated immature cartilage (**). (B) Pathologic examination of graft biopsy specimens (hematoxylin-eosin-safron stain at original magnification ×100) shows the regeneration of mature cartilage. (C) Regeneration of cartilage within the graft was demonstrated by positive immunodetection of (top row) type II collagen and (bottom row) Sox9-specific markers. The aortic matrix at time of implantation was used as a negative control. (D) Chimerism study from neotissues samples by real-time polymerase chain reaction (PCR) for the sex-determining region Y gene exhibited the absence of donor DNA, suggesting the disappearance of donor cells from the cryopreserved aortic allograft (CAA). (CF = curve fitting; RFU = relative fluorescent units.) (E) The paracrine potential of the CAAs was assessed, and mediators released from the CAAs were shown to exert significant proangiogenic (ie, a 30-fold increase in the number of pseudotubes compared with the control) and chemoattractant (ie, a ninefold increase in the number of migrated cells compared with the control) effects. (F) Secretome analysis of the CAAs revealed a massive release of proangiogenic, chemoattractant, proinflammatory/immunomodulatory, and growth factors such as angiopoietin 2, fibroblast growth factor (FGF-1), vascular endothelial growth factor c (VEGF-c), interleukin (IL) 1Ra, 6, 8, and 15, regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein 1 (MCP-1), hepatocyte growth factor (HGF), and granulocyte-colony stimulating factor (G-CSF). (BMP = bone morphogenetic protein; EGF = endothelial growth factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = interferon; MIG = monokine induced by γ interferon; MIP = macrophage inflammatory protein; TNF-α = tumor necrosis factor-α.) The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Biological studies of regenerated tracheas and implanted aortic matrices. (A) Pathologic examination of graft biopsy specimens (hematoxylin-eosin-safron stain at original magnification ×50) shows a regenerated continuous mixed epithelium (*) associated with some clusters of regenerated immature cartilage (**). (B) Pathologic examination of graft biopsy specimens (hematoxylin-eosin-safron stain at original magnification ×100) shows the regeneration of mature cartilage. (C) Regeneration of cartilage within the graft was demonstrated by positive immunodetection of (top row) type II collagen and (bottom row) Sox9-specific markers. The aortic matrix at time of implantation was used as a negative control. (D) Chimerism study from neotissues samples by real-time polymerase chain reaction (PCR) for the sex-determining region Y gene exhibited the absence of donor DNA, suggesting the disappearance of donor cells from the cryopreserved aortic allograft (CAA). (CF = curve fitting; RFU = relative fluorescent units.) (E) The paracrine potential of the CAAs was assessed, and mediators released from the CAAs were shown to exert significant proangiogenic (ie, a 30-fold increase in the number of pseudotubes compared with the control) and chemoattractant (ie, a ninefold increase in the number of migrated cells compared with the control) effects. (F) Secretome analysis of the CAAs revealed a massive release of proangiogenic, chemoattractant, proinflammatory/immunomodulatory, and growth factors such as angiopoietin 2, fibroblast growth factor (FGF-1), vascular endothelial growth factor c (VEGF-c), interleukin (IL) 1Ra, 6, 8, and 15, regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein 1 (MCP-1), hepatocyte growth factor (HGF), and granulocyte-colony stimulating factor (G-CSF). (BMP = bone morphogenetic protein; EGF = endothelial growth factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; IFN = interferon; MIG = monokine induced by γ interferon; MIP = macrophage inflammatory protein; TNF-α = tumor necrosis factor-α.) The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 In vivo airway tissue engineering—regenerative mechanisms. After implantation for the replacement of damaged airways, remaining viable aortic matrix cells released proangiogenic, chemoattractant, and proinflammatory/immunomodulatory and growth factors, which promoted local and general progenitor/stem cell homing. The human body was used as a natural bioreactor, thus allowing the regeneration of epithelium and cartilage within the matrix from recipient cells. The Annals of Thoracic Surgery 2017 103, 1631-1640DOI: (10.1016/j.athoracsur.2016.11.027) Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions