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J Thorac Cardiovasc Surg 2004;128:638-641
© 2004 The American Association for Thoracic Surgery
Brief communication |
a Department of Thoracic and Vascular Surgery, Heidehaus Hospital, Medical School Hannover, Hannover, Germany
b Biothoracic Surgical Laboratory (Leibniz Research Labs for Biotechnology and Artificial Organs [LEBAO]), Medical School Hannover, Hannover, Germany
Received for publication January 18, 2004; revisions received February 8, 2004; accepted for publication February 12, 2004.
* Address for reprints: Paolo Macchiarini, MD, PhD, Department of Thoracic and Vascular Surgery, Heidehaus Hospital, Hannover Medical School, Am Leineufer 70, D-30419 Hannover, Germany
pmacchiarini{at}compuserve.com
Airway defects occurring at the anastomotic site after carinal pneumonectomy are associated with persistent contamination between airway and pleural spaces, mediastinal spaces, or both and difficulties in the re-expansion of and possible aspiration into the residual lung. Unfortunately, therapeutic interventions are limited, and the outcome is often fatal.1 An ideal solution would be to generate an airway segment or surface to be implanted after achieving control of the infection and aspiration. Tissue-engineered airway is about the only technique of the many attempts at tracheal replacement that seems to offer any real promise.2 It applies the principles of engineering and life sciences toward the development of biologic substitutes that restore, maintain, or improve tissue function and offers the potential to create replacement structures from biodegradable scaffolds and autologous cells.3 We here describe the first clinical application of a tissue-engineered airway patch.
Clinical summary
A 58-year-old man was admitted in April 2003 complaining of general weakness, coughing up of pus, temperature of greater than 39°C, shortness of breath, and intolerable halitosis. He had undergone a right completion carinal pneumonectomy and radical lymphadenectomy for a relapsing non–small cell lung cancer pathologically staged as T4 N0 M0 in March 2003. He had had an upper bilobectomy and adjuvant radiation therapy (60 Gy) for an non–small cell lung cancer of equal histotype staged as T3 N2 in 1999. On chest radiography, the air-fluid pleural level in the postpneumonectomy space vanished, and the contralateral left lower lobe showed infiltrative signs suggestive of aspiration pneumonitis. Bronchoscopy showed a complete dehiscence of the ventrolateral aspect of the tracheobronchial anastomosis measuring 2 x 2 cm, communicating directly with the residual pleural space. Because Pseudomonas aeruginosa strains were found in the pleural space and blood, the diagnosis of pleural empyema and pyosepticemia was made, and the decision was taken to perform both ventral and dorsal open thoracostomies. The patient was further treated medically with the intent to sterilize the residual pleural space, prevent bacterial contamination of the residual left lung, and obtain a spontaneous closure of the anastomotic dehiscence.
The patient's general conditions improved slowly to an extent that his pleural space was uncontaminated, and his pyosepticemia resolved. However, on the basis of the previous bad clinical experiences,1 written informed consent was obtained to take, after achievement of local anesthesia, tissue samples at the thoracostomy sites with the intent to generate a bioengineered airway tissue that could then be transplanted to close the anastomotic defect (Figure 1). The patient was then discharged. We isolated muscle cells and fibroblasts from the biopsy samples by means of trypsin–ethylenediamine tetraacetic acid digestion and expanded the cultured cells in vitro. After 3 weeks (third cell passage), 1.5 million cells were seeded on a 24 x 36–mm matrix (5% muscle cells/95% fibroblasts). This carrier structure consisted of a collagen network that was generated from a decellularized porcine proximal jejunum segment (Figure 2, A and B). The resulting bioartificial construct was incubated for another 3 weeks in a bioreactor to control cell proliferation and to allow functional tissue formation by extracellular matrix turnover. Its maximal in vitro tolerance to pressure forces was then evaluated and found to be 300 mm Hg.
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Results
The patient can perform regular physical activity, enjoys hunting, and speaks with a sturdy voice. His quality of life has returned to normal. Clinical examination has been unremarkable, as has postpneumonectomy lung function. Control endoscopy on the fifth postoperative day showed a tight airway covered by a normal mucosa and a graft that was laterally rigid but longitudinally flexible, therefore synchronizing the inspiratory and expiratory movements. The graft's endoluminal aspect was surfaced with viable ciliated respiratory epithelium: its cellular density was 80% of that of the native trachea, and cell viability was almost 100%.
Outpatient endoscopies on the 3rd, 6th, and 12th postoperative weeks confirmed the above early postoperative findings and showed that the graft was airtight and surfaced with autologous ciliated respiratory epithelium (Figure 2, C and D), with no evidence of chronic inflammation, granulation tissue, infection, or erosion. Vascular ingrowth was detectable from the patch margins as soon as by the 6th week and completed by the 12th postoperative week. After 12 weeks, the entire patch was functionally and morphologically completely integrated into the adjacent airway. Chest computed tomography documented complete filling of the right pleural cavity.
Discussion
Tissue engineering implies formation of manmade functional biologic organs or tissue replacements by autologous cells introduced into a framework of biodegradable or biologic carrier structures, the so-called matrices.3 The advantages of the matrices are their biocompatibility, bioabsorbability, nonimmunogenity, support of cell attachment and growth, and ability to induce angiogenesis.
The tissue-engineered airway patch used here was made from autologous muscle cells and fibroblasts seeded on a sufficiently large (24 x 36 mm) matrix consisting of a collagen network generated from a decellularized porcine proximal jejunum segment. This bioartificial graft was then successfully clinically transplanted. The time frame needed to prepare it was clinically satisfactory because it allowed the infection of the residual pleural space and contralateral aspiration pneumonitis to subside, the patients' general conditions to improve, and the defect to stabilize. Its technical transplantation was surgically straightforward, avoided the very risky mediastinal dissection,1 and immediately guaranteed an airtight airway. Repeated bronchoscopies proved permanent closure of the defect and evidenced the graft's neovascularization in vivo. Most interestingly, however, was the demonstration that the tissue-engineered patch (1) was reseeded with functional ciliated respiratory epithelium, (2) had a cellular density equal to 80% of the native trachea, and (3) had almost entirely viable cells, and this was within the fifth postoperative day. This provides definitive evidence that a tissue-engineered airway patch with the dimensions used here can functionally survive and completely fills all requirements for an airway patch. A possible explanation for this phenomenon could be that the ingrowth of the respiratory epithelium from the normal tracheal ends alone was favored by the permanent viability of the bioengineered tissue. If this hypothesis holds true, there is no need for epithelial coverage and direct or indirect revascularization for tissue-engineered airway grafts of the dimensions used above.5
Conclusions
This anecdotal but encouraging experience unlocks the door for the clinical application of bioengineered airway tissue in other pediatric and adult pathologies in which therapeutic interventions are limited.4
References
This article has been cited by other articles:
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  P. Jungebluth, T. Go, A. Asnaghi, S. Bellini, J. Martorell, C. Calore, L. Urbani, H. Ostertag, S. Mantero, M. T. Conconi, et al. Structural and morphologic evaluation of a novel detergent-enzymatic tissue-engineered tracheal tubular matrix J. Thorac. Cardiovasc. Surg., September 1, 2009; 138(3): 586 - 593. [Abstract] [Full Text] [PDF]
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D. Fabre, S. Singhal, V. De Montpreville, B. Decante, S. Mussot, O. Chataigner, O. Mercier, F. Kolb, P. G. Dartevelle, and E. Fadel Composite cervical skin and cartilage flap provides a novel large airway substitute after long-segment tracheal resection J. Thorac. Cardiovasc. Surg., July 1, 2009; 138(1): 32 - 39. [Abstract] [Full Text] [PDF]
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 J. Schanz, M. Hampel, H. Mertsching, and T. Walles Experimental Tracheal Patching Using Extracellular Matrix Scaffolds Ann. Thorac. Surg., April 1, 2009; 87(4): 1321 - 1322. [Full Text] [PDF]
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T. Walles, V. Steger, H. Wurst, K.-D. Schmidt, and G. Friedel Pumpless extracorporeal gas exchange aiding central airway surgery. J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1372 - 1374. [Full Text] [PDF]
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P. Macchiarini, M. Altmayer, T. Go, T. Walles, K. Schulze, I. Wildfang, A. Haverich, M. Hardin, and Hannover Interdisciplinary Intrathoracic Tumor Tas Technical Innovations of Carinal Resection for Nonsmall-Cell Lung Cancer Ann. Thorac. Surg., December 1, 2006; 82(6): 1989 - 1997. [Abstract] [Full Text] [PDF]
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H. C. Grillo Bioengineered airway tissue J. Thorac. Cardiovasc. Surg., May 1, 2005; 129(5): 1208 - 1208. [Full Text] [PDF]
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T. Walles, B. Giere, M. Hofmann, J. Schanz, F. Hofmann, H. Mertsching, and P. Macchiarini Experimental generation of a tissue-engineered functional and vascularized trachea J. Thorac. Cardiovasc. Surg., December 1, 2004; 128(6): 900 - 906. [Abstract] [Full Text] [PDF]
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