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Ann Thorac Surg 1999;68:339-342
© 1999 The Society of Thoracic Surgeons

Original Articles

Prevention of postoperative air leakage from lungs using a purified human collagen membrane–polyglycolic acid sheet

Toru Tsuda, MDa, Tatsuo Nakamura, MDa, Yasumichi Yamamoto, MDa, Masayoshi Teramachi, MDa, Tetsuya Kiyotani, MDa, Yong Ho Lee, MDa, Yasuhiko Shimizu, MDa

a Department of Artificial Organs, Research Center for Biomedical Engineering, Kyoto University, Kyoto, Japan

Address reprint requests to Dr Tsuda, Departments of Artificial Organs, Research Center for Biomedical Engineering, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Human amnion has useful biomedical applications because it contains a large amount of human collagen fibers. We prepared purified human collagen membrane (HCM) from human amnion and used it to develop a new sheet by combining it with synthetic bioabsorbable polyglycolic acid (PGA) mesh. We evaluated its efficacy in preventing air leakage from the lungs of dogs.

Methods. In 20 dogs, HCM-PGA sheet (n = 5), sheets using fibrin glue with a separate application method (n = 5), a mixed application method (n = 5), and fibrin glue alone (n = 5), were used as dressing materials after partial lung resection.

Results. The HCM-PGA sheet using fibrin glue with a separate application method was shown to be significantly more effective by an air leakage pressure test than the other three methods. These results indicate that the HCM-PGA sheet is useful for preventing air leakage from the lung.

Conclusions. The HCM-PGA sheet is more effective than conventional fibrin glue for controlling postoperative air leakage.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
It is difficult to control air leakage after pulmonary operations, especially in patients with emphysematous lung disease. To prevent the formation of postoperative lung fistulas, fibrin glue has been used widely intraoperatively to control air leakage. However, if fibrinolysis occurs within a few days, air leakage is often observed during the postoperative course. Bovine pericardium or bioabsorbable sheets have also been used to prevent air leakage, but the suturing of such sheets often causes volume loss and deformity of the sutured lung. Moreover, it is often difficult to control air leakage from the needle holes by the conventional chest drainage method. We therefore developed a human collagen membrane (HCM) made from human amnion and used it to prepare a new kind of sheet by combining it with a synthetic bioabsorbable mesh of polyglycolic acid (PGA) for use as a new dressing material. We evaluated its efficacy by comparing it with conventional fibrin glue in animals for prevention of air leakage.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Amniotic membrane along with chorionic membrane was obtained from freshly delivered human placenta, and the two membranes were separated by stripping. To eliminate the antigenicity of the membrane, the surface cells were removed by treatment with 0.1% ficin. The membrane was then rinsed with phosphate buffer solution. Polyglycolic acid mesh with a pore size of 0.89 x 0.97 mm was immersed in 2.5% gelatin solution, and the membrane was then pasted on both surfaces of the mesh to give a three-layered sheet (Fig 1), which was then cross-linked by dehydrothermal treatment 140°C for 24 hours. Just before use, sterilization was done with ethylene oxide gas. In the strict sense, this membrane is not the original amnion but human collagen membrane.



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  		Fig 1. Human collagen membrane–polyglycolic acid sheet. Human collagen membrane is pasted on the bilateral surface of PGA mesh using gelatin, giving three layers.

 
Twenty female adult beagles weighing 7 to 10 kg were used. Anesthesia was induced by intramuscular administration of ketamine hydrochloride and xylazine. Endotracheal intubation was performed, and respiration was maintained by a volume controlled respirator. A right thoracotomy was done, followed by a 50 x 20-mm partial resection of the middle lobe. Ampicillin (1 g) was given intravenously on the day of the procedure. For repair of the partial defect of the lung, the following three methods were used.

(1) In five dogs, the defect was covered with a HCM-PGA sheet 50 x 20 mm, and its four corners were sutured with 5-0 Prolene (Ethicon, Somerville, NJ). (2) The defect was covered with an HCM-PGA sheet using fibrin glue (Beriplast P; Behringwerke, Germany). Two types of fibrin glue application were used. In the mixed application (5 dogs), the HCM-PGA sheet was placed over the defect, and a mixture of solution A (thrombin powder + aprotinin solution) and solution B (thrombin powder + calcium chloride solution) was applied over its surface. In the separate application (5 dogs), first, solution A was applied to the defect, and the HCM-PGA sheet was placed over it. Then, solution B was applied over the sheet (Fig 2). (3) The defect was treated with fibrin glue only in 5 dogs.



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  		Fig 2. Macroscopic view of the partial resection defect repaired with the HCM–PGA sheet using fibrin glue.

 
Pulmonary air leakage pressure was measured just after repair of the defect. Differences between groups were evaluated statistically using Student’s t test, and p values of 0.05 or less were considered significant. The animals were sacrificed at 4 and 8 weeks postoperatively to identify the histologic changes that had occurred. Each part of the defect was resected and examined grossly and microscopically. All operations and euthanasia were done in accordance with the Animal Welfare Regulation Guidelines of Kyoto University Animal Experimentation Committee (1989).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Prevention of air leakage
Before repair of the partial resection defects, air leakage began at an airway pressure of 10 to 15 cm H2O. The airway pressure at which air leakage began at the defect was defined as the air leakage pressure in this study. In the HCM-PGA sheet group, the air leakage pressure (mean ± standard deviation) was 40.0 ± 0.00 cm H2O. The prevention of air leakage was quite satisfactory (Fig 3). In the HCM-PGA sheet plus fibrin glue group, the air leakage pressure was 39.0 ± 5.48 cm H2O for the mixed application method and 44.0 ± 2.24 cm H2O for the separate application method. The air leakage pressure after separate application was significantly higher than that after mixed application (p < 0.05). In the fibrin glue group, the air leakage pressure was 18.0 ± 2.74 cm H2O, which was significantly lower than that in any of the other groups (p < 0.05). Irrespective of the treatment methods, no dog died of pulmonary air leakage postoperatively.



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  		Fig 3. Comparison of pulmonary air leakage pressure between repaired HCM-PGA sheet, HCM-PGA sheet + fibrin glue by separate application (sheet + glue Separate Ap), that by mixed application (sheet + glue Mixed Ap), and fibrin glue alone (cm H2O). * indicates the statistical significance (p <= 0.05) between two groups.

 
Macroscopic observation
In the HCM-PGA sheet groups, fibrous adhesions were seen in the repaired area and in the opposite chest wall at both 4 and 8 weeks, although the adhesion in the fibrin glue only group was less marked than that of other two groups. Neither local infection nor bleeding was observed in any group. Wound healing was also satisfactory in all dogs (Fig 4).



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  		Fig 4. Macroscopic view 8 weeks postoperatively. Fibrous adhesion is evident between the repaired area and in the opposite chest wall (human collagen membrane-polyglocolic acid sheet with fibrin glue was used).

 
Microscopic observation
The implanted HCM was still recognizable by microscopic observation at 4 weeks, but it was not evident at 8 weeks postoperatively. The PGA mesh was recognizable at both 4 and 8 weeks. The outer surfaces of the implanted HCM-PGA sheet were covered with regenerated pleural tissue at 4 weeks. A slight inflammatory reaction was seen in the tissue surrounding the HCM-PGA sheet in the groups that received HCM-PGA only and HCM-PGA plus fibrin glue. The degree of the inflammatory reaction was almost the same in both groups. (Fig 5).



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  		Fig 5. Microscopic view 4 weeks postoperatively. (Hematoxylin and eosin stain, original magnification x 40). The implanted human collagen membrane–polyglycolic acid mesh was still evident at 4 weeks but not at 8 weeks. Slight inflammatory change is seen. (Human collagen membrane–polyglycolic acid sheet with fibrin glue was used).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Human amnion is a promising biomaterial and is contained in freshly delivered human placenta. Such collagen membranes have been used to prevent adhesion of the pelvic peritoneum [1–3], intestine [4], pericardium [5], or vagina [6–9].

The final form of the fetal membrane is an inner amniotic membrane consisting of a single layer of ectodermally derived amnion cells fixed firmly to a collagen-rich mesenchymal layer six to eight cells thick, which is loosely attached to the chorion, consisting of compressed trophoblastic tissue of the chorion laeve and mesenchymal tissue [10]. The main component of human amnion is collagen, in which the ratio of type I to type III is 44:56 [11]. It also contains a small amount of type IV and V collagen [10].

We removed the surface cells from human amnion by treatment with ficin. Because this cell component is removed, the remaining membrane can be regarded as pure human collagen. In our previous study [12], we created a model of pulmonary pleural defects in animals, and plain HCM with several methods of simple attachment was used to repair the defect and evaluate the effectiveness of HCM. The air leakage test showed that the tolerance of the membrane to high pressure occurred in the following order: HCM plus fibrin glue by separate application was more effective than HCM alone, followed by HCM plus fibrin glue by mixed application, and least effective was fibrin glue. Those results suggested that HCM plus fibrin glue placed by separate application was satisfactory for prevention of air leakage from the lung [12]. During the experiment we found that attachment of the HCM through the effect of surface tension was satisfactory, but that the membrane slipped easy and wrinkled during handling because it was thin and fragile. Moreover, it cannot be sewn because of its weak tearing strength. Consequently, we developed a three-layered membrane made from HCM combined with synthetic PGA mesh.

PGA is a synthetic, absorbable, high-molecular-weight polymer. Nakamura and colleagues [13] have reported the reliability and superiority of PGA in comparison with conventional nonabsorbable pledgets in animal experiments. PGA sheets and pledgets are now used widely in pulmonary surgery. Although natural materials such as bovine pericardium, porcine skin, and porcine cardiac valves are used more commonly than synthetic high-molecular-weight materials, immunologic reactions caused by their intrinsic allopeptides are still unavoidable. Although autografts naturally have less antigenicity than allografts, acquisition of autografts is often difficult, and their quantities are insufficient for clinical implantation. Therefore, we focused on human amnion, which has less antigenicity and a lower tendency to infiltrate into surrounding tissue when used as a graft. We developed a three-layered membrane made from HCM combined with PGA mesh as a new biomaterial. The thickness and rigidity of this sheet can be controlled by changing the pore size or fiber thickness of the PGA mesh, and the membrane can be sewn and used for repair of more complex surgical defects. In the present study, as a model of a more complex surgical application, we used this new membrane to repair defects produced by partial lung resection. The operative procedure with this three-layered membrane was easier than that using the plain membrane in the previous study.

The air leakage test showed that the tolerance of the HCM-PGA sheet to high pressure occurred in the following order: the HCM-PGA sheet plus fibrin glue by separate application was most tolerant, followed by the HCM-PGA sheet alone, then the HCM-PGA sheet plus fibrin glue by mixed application, and least effective was fibrin glue. In terms of air leakage prevention, use of the HCM-PGA sheet and HCM-PGA sheet plus fibrin glue was significantly more effective than fibrin glue alone (p < 0.05).

When fibrin glue was applied to the lung, gel formation was observed in a few seconds. When fibrin glue was applied to the defect, coagulation of the fibrin glue prevented it from permeating into the defect, and the glue became detached from the surface of the defect when the airway pressure was high.

On the other hand, the HCM-PGA sheet plus fibrin glue attached by separate application gradually permeated into the tissue of the defect. The HCM-PGA sheet was then placed over the defect and allowed to adapt to solution A. Finally, gel formation was induced with solution B. This might be why the separate application method was more effective than the mixed application. The air leakage test showed no significant difference between use of the HCM-PGA sheet plus fibrin glue by mixed application and use of the HCM-PGA sheet alone.

The standard deviation for the HCM-PGA sheet plus fibrin glue group (mixed application) was higher than in the other groups, perhaps because the fibrin glue layer reduced the compliance between the HCM-PGA sheet and the defect, and the surface of the fibrin glue layer on the sheet was not flat. The present findings suggest that the most useful method for prevention of air leakage is application of the HCM-PGA sheet plus fibrin glue by separate application. Although the HCM is mechanically too weak to suture and slips easily and becomes wrinkled on the pulmonary surface during handling, the HCM-PGA sheet can be used as a substitute pleura for a pulmonary defect of any depth or width. Furthermore, we think that the HCM-PGA sheet has wide applications for suture reinforcement in fragile tissues such as lung. If the HCM-PGA sheet is applied to a pleural defect with fibrin glue, unnecessary lung volume loss from suturing can be avoided. Thus application of the HCM-PGA sheet is a useful method for preventing pulmonary air leakage as a novel substitute pleura.


   Acknowledgments
 
We are grateful to Yasuyuki Kitagawa and Minako Ishii for their assistance. This study was supported by a grant from the Japan Society for the Promotion of Science, "Research for the Future" program, JSPS-RFTF 96100203.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Erdener A., Ulman I., Ilhan H., Soydan S. Amniotic membrane wrapping. Eur J Pediatr Surg 1992;2:26-28.[Medline]
  2. Massee J.S., Symmonds R.E., Dockerty M.B., Hallenbeck G.A. Use of fetal membranes as replacement for pelvic peritoneum after pelvic exenteration in the dog. Surg Forum 1962;13:407-408.
  3. Gharib M. Repair of prenatally ruptured omphalocele and the paraumbilical abdominal wall defect with the infant’s own fetal membranes. Münchener Medizinische Wochenschrift 1975;117:1555-1558.
  4. Beral M., Gokqora H., Erekul S., Dindar H., Yucesan S. Human amniotic membrane as an intestinal patch for neomucosal growth in the rabbit model. J Pediatr Surg 1992;27:597-601.[Medline]
  5. Muralidharan S., Gu J., Laub G.W., Cichon R., Daloisio C., McGrath L.B. A new biological membrane for pericardial closure. J Biomed Material Res 1991;25:1201-1209.
  6. Burger K. Artificial vaginal reconstruction with the help of amnion. Zentralb Gynaecol 1937;61:2437-2440.
  7. Tracer M.L., Katz M., Veridiano N.P. Vaginal epithelialization with human amnion. Obstet Gynecol 1979;54:345-349.[Abstract/Free Full Text]
  8. Young R.L., Mason B.A., Cota J., Wheeler J.M., Zund G. The use of amniotic membrane graft to prevent postoperative adhesions. Fertil Steril 1991;55:624-628.[Medline]
  9. Trelfold J.D., Hanson F.W., Anderson D.G. The feasibility of making an artificial vagina at the time of anterior exenteration. J Oncol 1973;28:398-401.
  10. Wynn R.M., French G.L. Comparative ultrastructure of the mammalian amnion. Obstet Gynecol 1968;31:759-774.[Free Full Text]
  11. Liu B., Harrell R., Xu Z., Dresden M.H., Spira M. Immune response to {gamma}-irradiated injectable human amnion and human skin collagens in the rat. Arch Dermatol 1989;125:1084-1089.[Abstract]
  12. Tsuda T., Kitagawa Y., Teramachi M., et al. Prevention of air leakage from operated lungs with purified human collagen membrane. Jpn J Artif Organs 1996;25:417-420.
  13. Nakamura T., Shimamoto T., Hyon S.H., Watanabe S., Shimizu Y., Ikada Y. Application of bioabsorbable pledgets to tracheal surgery. Proceedings of the Third World Biomaterials Congress, April 21–25, 1988. Kyoto, Japan: Business Center for Academic Societies, Japan, 1988:277.
Accepted for publication March 6, 1999.




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