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Ann Thorac Surg 1996;61:1070-1073
© 1996 The Society of Thoracic Surgeons

Original Article: General Thoracic

Colored Collagen Is a Long-Lasting Point Marker for Small Pulmonary Nodules in Thoracoscopic Operations

Hiroaki Nomori, MD, Hirotoshi Horio, MD

Department of Surgery, Saiseikai Central Hospital, Tokyo, Japan

Accepted for publication December 1, 1995.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. To locate small deep pulmonary nodules under thoracoscopy, we developed a long-lasting point marker termed ``colored collagen.''

Methods. Colored collagen is composed of 0.8% atelocollagen, 5% methylene blue, and 32% contrast medium. The affinity between atelocollagen and methylene blue was examined in a washing test using 2 mol/L of NaCl. For clinical application, a computed tomography-guided colored collagen injection was performed in 11 patients to localize 11 deep pulmonary nodules, which were less than 20 mm in diameter.

Results. The washing test showed that atelocollagen and methylene blue combined with each other firmly. An experimental study using rabbit lung showed that the colored collagen stayed at the injected site for 10 days without toxicity. In clinical application, the colored collagen could be seen as a clear spot using thoracoscopy 1 to 4 days after the injection in all of the 11 pulmonary nodules. There was no complication except for a slight pneumothorax in 2 patients.

Conclusions. The colored collagen, because it stays in the injected site for a long time, solves the problem of the single dye injection method, which requires both a computed tomographic scan and an operating room simultaneously, and also the colored collagen, because of its point dyeing, can mark the nodule more accurately than a single dye.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
In recent years, thoracoscopic surgical techniques have been used in diagnostic excisional biopsies of pulmonary nodules as well as therapeutic resection of peripheral lung cancers. For small or deeply situated pulmonary nodules, however, a major factor limiting the success of thoracoscopic resection is the difficulty in locating the target nodule due to the lack of digital palpation. To locate pulmonary nodules under thoracoscopy, computed tomography (CT)-guided dye injection techniques have been reported [1–3]. However, the single dye technique has the complication of requiring both a CT scan and an operating room available simultaneously, because of its rapid diffusion around the tissue immediately after the injection. To solve this problem, we have developed a marker termed ``colored collagen'' that is composed of atelocollagen, methylene blue, and a contrast medium, using the characteristic of atelocollagen to stay at the injected site permanently without complication [46]. In the present study, we demonstrate the results of this experimental study and clinical application.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Colored Collagen
Colored collagen is composed of 0.8% atelocollagen (Koken Co, Tokyo, Japan), 10% methylene blue, and 32% nonionic contrast (iohexol; Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan), dissolved in phosphate buffered saline (pH 7.4).

Experimental Studies
WASHING TEST.
The affinity between atelocollagen and methylene blue was examined as follows: (1) 2 mol/L of NaCl solution was added to 0.5 mL of colored collagen, stirred, and then centrifuged at 3,000 rpm for 10 minutes, (2) after this washing was done 10 times, the sedimented colored collagen was heated at 80°C for 10 minutes to denature it, and was diluted to 104 times, and (3) its photoabsorbance was measured by a Hitachi U-2000 Spectro-Photometer (Hitachi Co, Tokyo, Japan). Unwashed denatured colored collagen was used as a control.

IN VIVO STUDY.
New Zealand white rabbits weighing 2 to 2.5 kg were anesthetized using pentobarbital. Concentrations of the atelocollagen in the colored collagen were adjusted to 0.1, 0.2, 0.5, 0.8, 1.0, and 2.0%. One milliliter of colored collagen in each concentration of atelocollagen was injected percutaneously into the lung of a rabbit. The rabbits were killed 10 days after the injection to check for the presence of colored collagen in the lung. This experiment was repeated three times.

Patients
Between April 1995 and October 1995, preoperative marking with colored collagen was performed in 11 patients undergoing thoracoscopy to locate 11 pulmonary nodules less than 20 mm in size and situated away from the pleural surface (Table 1Go). The maximum diameter of the nodules ranged from 4 to 20 mm, averaging 13.4 mm. As determined by CT scanning, the distance from the peripheral edge of the nodule to the nearest pleural surface ranged from 5 to 28 mm, averaging 12.6 mm. There were 7 men and 4 women ranging in age from 43 to 80 years. All had initially undergone conventional diagnostic CT examination of the thorax with a standard 10-mm section slice. The nodules were located in the right upper lobe in 2 patients, right middle lobe in 1, right lower lobe in 3, left upper lobe in 3, and left lower lobe in 2 patients. Eight of the 11 patients underwent thoracoscopic wedge resection for pathologic diagnosis because the previous transthoracic or transbronchial biopsy had not given any diagnosis. The other 3 patients had a previous histopathologic diagnosis as primary lung cancer and a therapeutic indication for thoracoscopic wedge resection because of the patients' impaired lung function.


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  		Table 1. . Characteristics of Pulmonary Nodules
 
Technique
The original diagnostic CT study was reviewed to select a colored collagen injection site. The shortest distance from the nodule to the thoracic wall was selected to be the injection site. The patient was placed on the CT table in a suitable position (supine or prone). After local anesthesia of the thoracic wall, the pleural side of the lesion was punctured with a 23-gauge needle. Once the needle tip was identified as within the nodule or just in contact with it, we drew the syringe to confirm that blood had not flowed backward, and then injected 0.5 to 1.0 mL (mean, 0.8 mL) of colored collagen. Subsequent CT images were obtained after the procedure to confirm the injected site of colored collagen relative to the nodule (Fig 1Go). The presence of all of the injected colored collagen was confirmed in a chest roentgenogram the morning of operation, because it was visible by contrast medium. Thoracoscopy was performed 1 to 4 days (mean, 2.5 days) after colored collagen injections.



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  		Fig 1. . (A) Computed tomographic scan showing a nodule 0.7 cm in size (indicated by arrowhead) at the left lower lobe. (B) Colored collagen was injected around the nodule.

 

   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
The peak of methylene blue photoabsorbance was 660 nm. The result of the washing test showed no difference in the photoabsorbance value between the washed colored collagen and the control (Fig 2Go).



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  		Fig 2. . The photoabsorbance was not different between the washed colored collagen (W) and a control test (C).

 
The results of the in vivo study using the rabbit lung showed that injection of colored collagen had no complication or toxicity. Colored collagen in all atelocollagen concentrations was located at the injected sites 10 days after injection (Fig 3Go). The optimum concentration of atelocollagen was 0.8% or 1.0%. In concentrations less than 0.5%, the color was too light to locate the marking site. Concentrations more than 1.5% were hard to inject because of high viscosity. Therefore, we used colored collagen of 0.8% atelocollagen concentration for clinical application.



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  		Fig 3. . The in vivo study using rabbit lungs showed that a colored collagen (indicated by tweezers) stayed locally at the injected site for 10 days.

 
All 11 pulmonary nodules were successfully located with colored collagen. There was no complication aside from a slight pneumothorax in 2 patients, who did not need thoracic drainage. There was no pain due to the stimulation of the pleura by the colored collagen itself. All of the injected colored collagen could be seen by chest roentgenogram at the injected sites in the morning of operation. In thoracoscopy, the colored collagen could be seen through the pleura as a clear spot in all 11 of the nodules and was a great help in locating the nodules (Fig 4Go). Ten of the 11 nodules could be resected through the trocar without thoracotomy. The remaining one nodule, which was located in the right lower lobe near the lower pulmonary artery, necessitated a mini-thoracotomy to prevent injury to the artery.



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  		Fig 4. . Thoracoscopy showed the point dyeing by colored collagen (indicated by arrows) 2 days after the injection (same patient as in Fig 1Go).

 
The resected specimens showed that the colored collagen had a clear margin with the surrounding lung tissue, which indicated that the colored collagen stayed locally without diffusion after injection (Fig 5Go). The injected colored collagen was shown as a fibrinlike substance, which did not obstruct the pathologic diagnosis of the lesion.



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  		Fig 5. . The resected specimen (same patient as in Figs 1 and 4GoGo) showed that the colored collagen (indicated by arrows) had a clear margin with the surrounding lung tissue. Pathologic diagnosis of the nodule was an intrapulmonary lymph node.

 
The pathologic diagnosis of the 11 nodules were inflammatory lesion in 6 patients, metastatic lung cancer in 1, primary lung cancer in 3, and intrapulmonary lymph node in 1 patient.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Several methods have been proposed to localize small pulmonary nodules under thoracoscopic surgical technique, such as CT-guided hook-wire techniques [3, 7–9], endoscopic ultrasound [10], and percutaneous injection of methylene blue solution [1–3]. However, these techniques have several problems. The hook-wire technique carries the risk of pneumothorax, pulmonary hemorrhage, and dislodgment of the wire from the lung by the time of thoracoscopy, and the trouble of requiring both CT and operating rooms simultaneously [3–6]. Intraoperative sonography has a failure rate of 40% in locating the nodule [10]. The previously reported dye injection method, due to its rapid diffusion around the tissue after the injection, has the following faults: (1) it requires both CT and operating rooms simultaneously and (2) the spot of injected dye is blurred [1, 2].

An atelocollagen, which has been generally injected in subcutaneous tissue, vocal cords, and urethral sphincter for cosmetic or functional purposes, has the characteristic of staying locally in the injected site permanently without complication [4–6]. Using this characteristic, we have developed a colored collagen for marking the small pulmonary nodules in thoracoscopic operations.

Vigorous washing using 2 mol/L of NaCl, which has the effect of separating the ionic combinations, indicated that the affinity between atelocollagen and methylene blue was quite firm and was not due to an ionic combination. The affinity is possibly due to the fibrous structure of atelocollagen itself, which is made up of three peptides ({alpha}-chain), each of which consists of approximately 1,000 amino acid residues [4]. The in vivo study using rabbits showed that the injection of colored collagen was safe and the colored collagen stayed locally without diffusion for 10 days, long enough for clinical application.

Clinical application showed that the injection of colored collagen had no complication aside from a slight pneumothorax. The injected colored collagen stayed as a local spot for a mean of 2.5 days, which was due to the characteristics of atelocollagen itself. Compared with the single dye solution, the colored collagen has two main advantages: (1) it is long-lasting at the injected site and solves the trouble of requiring both a CT and an operating room simultaneously and (2) its point dyeing at the injected site facilitates the detection of small pulmonary nodules more accurately and prevents the overresection of the normal lung around the nodule.

In the present study, the maximum distance from the nodule to the pleural surface was 28 mm. For a more deeply situated nodule than the presented cases, colored collagen, because of its characteristic of no diffusion, may have difficulty locating the nodule by visual localization. Colored collagen, however, by containing the contrast medium, can be also shown by intraoperative fluoroscopic examination. Therefore, it should be possible to locate and resect a more deeply situated pulmonary nodule that is marked by colored collagen by in addition using intraoperative fluoroscopy.

In conclusion, colored collagen is a more useful marker for small pulmonary nodules than a single dye solution because of its point dyeing over a long period of time.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank Mr Hiroshi Itoh (a general manager in Koken Co, Ltd, Tokyo, Japan) for assisting us in the experimental study.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Nomori, Department of Surgery, Saiseikai Central Hospital, 1-4-17 Mita, Minato-ku, Tokyo 108, Japan.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Wicky S, Mayor B, Cuttat JF, Schnyder P. CT-guided localizations of pulmonary nodules with methylene blue injections for thoracoscopic resections. Chest 1994;106:1326–8.
  2. Kerrigan DC, Spence PA, Crittenden MD, Tripp MD. Methylene blue guidance for simplified resection of a lung lesion. Ann Thorac Surg 1992;53:163–4.
  3. Shah RM, Spirn PW, Salazar AM, et al. Localization of peripheral pulmonary nodules for thoracoscopic excision. AJR 1993;161:279–83.
  4. Charriere G, Bejot M, Schnitzler L, Ville G, Hartmann DJ. Reactions to bovine collagen implant. Clinical and immunologic study in 705 patients. J Am Acad Dermatol 1989;21:1203–8.
  5. Ford CN, Martin DW, Warner TF. Injectable collagen in laryngeal rehabilitation. Laryngoscope 1984;94:513–8.
  6. Shortliffe LMD, Freiha FS, Kessler R, Stamey TA, Constantinou CE. Treatment of urinary incontinence by the periurethral implantation of glutaraldehyde cross-linked collagen. J Urol 1989;141:538–41.
  7. Gossot D, Miaux Y, Guermazi A, Celerier M, Frija J. The hook-wire technique for localization of pulmonary nodules during thoracoscopic resection. Chest 1994;105:1467–9.
  8. Mack MJ, Gordon MJ, Postma TW, et al. Percutaneous localization of pulmonary nodules for thoracoscopic lung resection. Ann Thorac Surg 1992;53:1123–4.
  9. Plunkett MB, Peterson MS, Landreneau RJ, Ferson PF, Posner MC. Peripheral pulmonary nodules: preoperative percutaneous needle localization with CT guidance. Radiology 1992;185:274–6.
  10. Shennib H, Bret P. Intraoperative transthoracic ultrasonographic localization of occult lung lesions. Ann Thorac Surg 1993;55:67–9.



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