Regenerative medicine offers new tools with which to tackle disorders for which there is currently no good therapeutic option. The trachea is an ideal organ in which to explore the clinical potential of tissue engineering because severe large airway disease is poorly managed by conventional treatments, and the success of a graft is determined only by its ability to conduct air lifelong: that is, whether it can become a sustainable biological conduit. We define the component parts of tissue engineering and review the experimental methods used to produce airway implants to date, including a recent successful, first-in-man experience.

Autologous tissue transfer, allografts and prosthetic replacements have so far failed to offer functional solutions for the treatment of long circumferential tracheal defects. Because of the shortcomings related with these strategies, interest has turned increasingly to the field of tissue engineering which applies the principles of engineering and life sciences in an effort to develop in vitro biological substitutes able to restore, maintain, or improve tissue and organ function. The advances in this field during the past decade have thus provided a new attractive approach toward the concept of functional substitutes and may represent an alternative to the shortage of suitable grafts for reconstructive airway surgery. This article gives an overview of the tissue engineering approach and of the encouraging strategies attempted so far in trachea regeneration.

BACKGROUND: The purpose of this study was to evaluate the feasibility of integrating an artificial, pumpless extracorporeal membrane ventilator (Novalung) to near static mechanical ventilation and its efficacy in patients with severe postresectional acute respiratory distress syndrome (ARDS) unresponsive to optimal conventional treatment. METHODS: Indications were severe postresectional and unresponsive acute respiratory distress syndrome, hemodynamic stability, and no significant peripheral arterial occlusive disease or heparin-induced thrombocytopenia. Management included placement of the arteriovenous femoral transcutaneous interventional lung-assist membrane ventilator, lung rest at minimal mechanical ventilator settings, and optimization of systemic oxygen consumption and delivery. RESULTS: Among 239 pulmonary resections performed between 2005 and 2006, 7 patients (2.9%) experienced, 4 +/- 0.8 days after 5 pneumonectomies and 2 lobectomies, a severe (Murray score, 2.9 +/- 0.3) acute respiratory distress syndrome unresponsive to 4 +/- 2 days of conventional therapy. The interventional lung-assist membrane ventilator was left in place 4.3 +/- 2.5 days, and replaced only once for massive clotting. During this time, 29%+/- 0.3% or 1.4 +/- 0.36 L/min of the cardiac output perfused the device, without hemodynamic impairment. Using a sweep gas flow of 10.7 +/- 3.8 L/min, the device allowed an extracorporeal carbon dioxide removal of 255 +/- 31 mL/min, lung(s) rest (tidal volume, 2.7 +/- 0.8 mL/kg; respiratory rate, 6 +/- 2 beats/min; fraction of inspired oxygen, 0.5 +/- 0.1), early (<24 hours) significant improvement of respiratory function, and reduction of plasmatic interleukin-6 levels (p < 0.001) and Murray score (1.25 +/- 0.1; p < 0.003). All but 1 patient (14%) who died of multiorgan failure were weaned from mechanical ventilation 8 +/- 3 days after removal of the interventional lung-assist membrane ventilator, and all of them were discharged from the hospital. CONCLUSIONS: The integration of this device to near static mechanical ventilation of the residual native lung(s) is feasible and highly effective in patients with severe and unresponsive acute respiratory distress syndrome after pulmonary resection.

BACKGROUND: The loss of a normal airway is devastating. Attempts to replace large airways have met with serious problems. Prerequisites for a tissue-engineered replacement are a suitable matrix, cells, ideal mechanical properties, and the absence of antigenicity. We aimed to bioengineer tubular tracheal matrices, using a tissue-engineering protocol, and to assess the application of this technology in a patient with end-stage airway disease. METHODS: We removed cells and MHC antigens from a human donor trachea, which was then readily colonised by epithelial cells and mesenchymal stem-cell-derived chondrocytes that had been cultured from cells taken from the recipient (a 30-year old woman with end-stage bronchomalacia). This graft was then used to replace the recipient's left main bronchus. FINDINGS: The graft immediately provided the recipient with a functional airway, improved her quality of life, and had a normal appearance and mechanical properties at 4 months. The patient had no anti-donor antibodies and was not on immunosuppressive drugs. INTERPRETATION: The results show that we can produce a cellular, tissue-engineered airway with mechanical properties that allow normal functioning, and which is free from the risks of rejection. The findings suggest that autologous cells combined with appropriate biomaterials might provide successful treatment for patients with serious clinical disorders. FUNDING: Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, Spain; Charles Courtenay-Cowlin Fund, University of Bristol; UK Arthritis Research Campaign; and the James Tudor Foundation.

OBJECTIVE: We compared conventional treatment with pumpless extracorporeal lung membrane (Interventional Lung Assist [iLA] Novalung; Novalung GmbH, Hechingen, Germany) support in a pig model of postpneumonectomy severe acute respiratory distress syndrome. METHODS: Adult pigs underwent a left thoracotomy without (group I) or with a left extrapericardial pneumonectomy and radical lymphadenectomy (groups II to V). After stabilization, pigs belonging to group II were observed only, whereas in those belonging to groups III to V, a surfactant-depletion severe (Pao(2)/Fio(2)< 100) postpneumonectomy acute respiratory distress syndrome was induced. This was followed by observation (group III); treatment with conventional therapy including protective ventilation, steroids, and nitric oxide (group IV); or femoral arteriovenous iLA Novalung placement, near-static ventilation, steroids, and nitric oxide (group V). Each group included 5 animals. Primary outcome was extubation 12 hours postoperatively or postpneumonectomy acute respiratory distress syndrome. RESULTS: A severe postpneumonectomy acute respiratory distress syndrome was obtained after 9 +/- 2 alveolar lavages over 90 +/- 20 minutes. In group V pigs, the iLA Novalung device diverted 17%+/- 4% of the cardiac output, permitted an oxygen transfer and carbon dioxide removal of 298.4 +/- 173.7 mL/min and 287.7 +/- 87.3 mL/min, respectively, and static ventilation (tidal volume, 2.2 +/- 1 mL/kg; respiratory rate, 6 +/- 2.9 breaths/min). All but 1 pig belonging to group V could be extubated compared with none in groups III and IV (P <.01), and only their lungs normalized cytokine release (P <.001) and surfactant (P <.03) and displayed fewer parenchymal lesions (P <.05). CONCLUSIONS: The pumpless extracorporeal lung membrane and near-static ventilation achieved a significantly better outcome than conventional treatment in this pig model of severe postpneumonectomy acute respiratory distress syndrome, probably because the injured lungs were not forced to work and this "rest" gave them more time to heal.

A 47-year-old man was admitted with recurrent autolimited bleeding arising from a cervical tracheostoma made 2 years earlier during a total laryngectomy. Stomal recurrence of the past laryngeal cancer invading the neighboring innominate artery was diagnosed by angiographic computer tomography and bronchoscopic biopsies. The malignant tracheostoma-innominate fistula was approached through an extended transversal supraclavicular incision, bilateral hemiclaviculectomy, and manubriectomy. It was treated with an anterior mediastinal tracheostomy with omental major transposition, right latissimus dorsi myocutaneous flap for tissue coverage, and brachiocephalic artery rerouting with cadaveric homograft. The patient was discharged on postoperative day 14 after an uneventful postoperative course.

Physicians' understanding of the anatomy, biology [9], and treatment outcome [12] for superior sulcus carcinoma has changed greatly during the last decade [2,3]. One of the major advances in this regard has been the introduction of anterior approaches for resection. These approaches increase the likelihood of complete resection and permit resection of tumors that were previously considered technically unresectable. Each approach must be understood in detail to avoid incomplete operations and life-threatening complications. These technical advances, with recent evidence that preoperative chemoradiotherapy leads to higher complete resection rates, overall survival, and local control than do radiation and surgery alone [32], have changed physicians' attitudes toward superior sulcus carcinomas, especially for those tumors (eg, T4) previously considered technically unresectable and oncologically incurable. It is hoped that, in the future, resection of disease invasion of the brachial plexus above C7 will be technically feasible [33], and that new drugs will reduce the risk of systemic relapse after resection.

BACKGROUND: The purpose of this study was to evaluate the long-term clinical and immunologic outcome of cryopreserved arterial allograft (CAA) revascularization of intrathoracic vessels invaded by malignancies. METHODS: Since January 2002, consecutive patients whose intrathoracic vessels were invaded by malignancies were operated on and revascularizion made using human lymphocyte antigen (HLA)- and ABO-mismatched CAAs. Immunologic studies were performed preoperatively, and 1, 3, 6, 12, and 24 months postoperatively. Postoperative oral anticoagulation therapy was not given. RESULTS: Twenty-six patients aged 53.1 +/- 15 years with a nonsmall-cell lung cancer (n = 10), invasive mediastinal tumors (n = 7), pulmonary artery sarcoma (n = 3), laryngeal (n = 2), or other rare lung neoplasms (n = 4) underwent operation. Cardiopulmonary bypass was used in 10 cases (38%), and all resections were pathologically complete. Revascularization was either for venous (n = 12) or arterial (n = 14) vessels, and a total of 30 allografts revascularized the superior vena cava (n = 6), pulmonary artery (n = 7), innominate vein (n = 3) or artery (n = 2), ascendent (n = 4) or descending (n = 1) aorta, and subclavian vein (n = 3) or artery (n = 4). Hospital morbidity and mortality were 50%(n = 13) and 3.8%(n = 1), respectively, all CAA unrelated. With a median follow-up of 18 months (range, 3 to 60+), 5-year survival and allograft patency were 84% and 95%, respectively. Preoperative anti-HLA antibodies were detected in 2 patients (7.7%) and a postoperative anti-HLA antibody response, clinically irrelevant, in 1 of 24 patients (4%). CONCLUSIONS: Revascularization of intrathoracic venous and arterial vessels in patients with malignancies using HLA- and ABO-mismatched CAA is technically feasible and clinically attractive because of no infection risk and postoperative anticoagulation, and excellent long-term survival, patency, and nonimmunogeneicity.

Laryngeal and tracheal transplantation have been proposed as treatments for irreversible airway disease for many years. Despite much research, there has only been one true laryngeal transplant reported. Although this was in many ways a success, several barriers remain before full clinical trials. There are issues over patient selection, reinnervation, immunosuppression, and cost-benefit. For the trachea, where finely tuned neuromuscular activity is not an issue, tissue-engineering probably represents the future. This overview discusses the arguments for and against laryngeal and tracheal transplantation and suggests ways of overcoming these barriers.

BACKGROUND: A small experimental animal model of postobstructive pulmonary hypertension (PH) providing insights in the physiopathology of this disease was developed. MATERIALS AND METHODS: Male Lewis rats were anesthetized and aleatory manipulated via a left thoracotomy with (group I, n = 10) or without (group II, n = 10) ligation of the left pulmonary artery. Animals were followed for 2 weeks and then sacrificed. Hemodynamic parameters and blood gases were recorded at baseline and 2 weeks after surgical procedure. RESULTS: Group I animals developed a significant (P < 0.01) PH (mean pulmonary artery pressure, 32 +/- 6 versus 16 +/- 2 mm Hg; pulmonary vascular resistance, 46 +/- 3 versus 21 +/- 2 mm Hg/mL/min; reduction of cardiac output, 75 +/- 3 versus 105 +/- 4 mL/min), compared to group II animals, and had a significant (P < 0.01) worse gas exchange (partial arterial pressure of O(2): 91 +/- 3 versus 439 +/- 24 mm Hg; partial arterial pressure of CO(2): 54 +/- 3 versus 42 +/- 2 mm Hg, on a fraction of inspired oxygen of 1.0), right ventricle hypertrophy (ventricle to left ventricle/septum ratio, 0.56 +/- 0.04 versus 0.45 +/- 0.04, P < 0.02) and less tolerance test (immobility time, 123 +/- 11 versus 61 +/- 8 s, P < 0.01) than group II animals. Histologically, ligated lungs showed postobstructive pulmonary vasculopathic abnormalities and bronchial-pulmonary artery hypertrophy, and the contralateral lung had initial signs of small vessel arteriopathy. CONCLUSIONS: The experimental model generated here successfully reproduced a PH morphologically and functionally similar to clinical postembolic PH and might be used for evaluating the physiopathology of postobstructive PH.

BACKGROUND: The generation of autologous tracheal implants by tissue-engineering techniques is a promising concept for otherwise untreatable patients. A functional cartilaginous backbone represents a prerequisite for any bioartificial tracheal graft. The aim of this study was to define suitable cell types and culture conditions for the generation of tracheal cartilage. METHODS: We obtained tracheal, costal, and auricular cartilage from porcine donor animals (n = 10). The chondrocytes were cultured two-dimensionally in cell flasks or mixed with a liquid collagen solution forming a three-dimensional culture system. Labeling with carboxy fluorescein diacetate succinimidyl ester (CFDA SE) and biochemical reduction of formazan served to determine cell viability and proliferation. The extracellular matrix produced by the chondrocytes was characterized by Western blot. RESULTS: The CFDA SE labeling proved viability and the MTT assays documented a proliferation of the chondrocytes over time in vitro. While the chondrocytes in the three-dimensional cell culture system produced hyaline cartilage composed of collagen II, the two-dimensional culture conditions resulted in nonspecific collagen synthesis. CONCLUSIONS: Chondrocytes grown in a three-dimensional matrix can effectively proliferate and produce cartilage and are viable for more than 2 weeks. Costal chondrocytes are suitable for tracheal cartilage tissue engineering.