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Ann Thorac Surg 2004;77:2177-2181
© 2004 The Society of Thoracic Surgeons
a Heart Centre University Hospital Ghent, Ghent, Belgium
b Department of Pathology, University Hospital Ghent, Ghent, Belgium
Accepted for publication May 8, 2003.
* Address reprint requests to Dr Van Nooten, Cardiac Surgery Department 5K12, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.
e-mail: guido.vannooten{at}rug.ac.be
Abstract
PURPOSE: The aim of the study is to explore the feasibility, patency, and histologic changes of a sutureless vascular anastomotic technique using biological glue as sole fixation method.
DESCRIPTION: Eight mongrel dogs (±15 kg) underwent direct reanastomosis of their transsected iliac arteries. Both ends were placed on a 5-mm balloon and the anastomosis was secured with biological glue (BioGlue, Cryolife, Kennesaw, GA). No intravascular suture material was used. All survivors were angiographically controlled for patency after 6 weeks and 3 months. Then the animals were euthanized and tissues were obtained for histologic and pathologic examination by light and electron microscopy.
EVALUATION: All procedures were successful except for 1 animal that died of uncontrollable bleeding at the anastomotic site. All first-time angiographically controlled grafts except three were patent. One animal showed manifest signs of fungal infection. Histology detected early granulocyte infiltration with an important enzymatic reaction adjacent to the surface of glue. Later on, the glue gradually regressed to disappear completely. Fibroblastic neointimal lining was noticed in most of the anastomoses, with some marked differences in the endothelium compared with normal.
CONCLUSIONS: Good permeability (57%) was observed in this new sutureless anastomotic technique in the canine model. In contrast to previous reported studies we noticed a clear enzymatic breakdown of the glue before total disappearance. It is not yet known to what extend use of the bovine glue was responsible for this phenomenon.
For more than a century, the golden standard to create patent vascular anastomoses was manual surgical suturing. Recently, minimally invasive totally endoscopic surgery using computer-enhanced techniques and robotics has been rapidly gaining interest. However, when using these methods, the time-consuming classic vascular suturing technique remains one of the most difficult acts to reproduce. To progress to true port-access surgery, alternative methods for joining two blood vessels are under investigation. In the past, several types of glue have been used to secure an anastomosis with disappointing results. Cyanoacrylic glues showed good tensile strength, but caused deterioration of the vascular wall and aneurysm formation [1]. The use of gelatin-resorcinol-formaldehyde (Cardial Technopole, St. Etienne, France) glue as a sealant yields a high redissection rate in aortic dissection repair as reported by Bingley and colleagues [2].
We describe results from the use of BioGlue (CryoLife Inc, Kennesaw, GA), a bovine albumin substrate, as surgical tool to perform sutureless vascular anastomoses in an experimental dog model.
Technology
BioGlue is a surgical adhesive that combines two agents with distinct properties (45% concentrated bovine albumin and 10% glutaraldehyde). The compound becomes active once the two components are mixed within the applicator gun by passing through a specially designed delivery tip. Full holding power is achieved within 2 minutes. The glue is approved for use in North America and Europe for the treatment of acute aortic dissection, for facilitating sutured arterial anastomoses or sealing of suture lines.
Technique
Eight mongrel female dogs, ex-breeders, underwent direct reanastomosis of both external iliac arteries following total section of the arteries. Average age was 6.9 years (range 4 to 10 years), average weight 15.3 kg (range 10 to 23 kg). No vaccines that had been in contact with bovine albumin were administrated previously to the animals. The dogs were fasted for 24 hours and premedicated. After the animal was positioned, a peripheral intravenous line was placed in the left upper limb. Then 15 mg/kg cephalosporin was injected intramuscularly for antibiotic prophylaxis, and maintenance intravenous crystalloid fluids were given. A three-lead electrocardiogram was used to monitor heart rate and rhythm. Propofol 0.5 mg/kg was administrated before tracheal intubation. Ventilation parameters were adjusted to keep the blood gas values within normal range. Anesthesia was maintained by intravenous propofol 4 to 8 mg/kg/h, fentanyl 1 µg/kg, and pancurorium 0.1 mg/kg for muscle relaxation. Incisions were made in both groins to expose the iliac arteries. Arteries were dissected and snared, 1 mg/kg heparin was administered, and the iliac artery clamped before transection. Both ends were fixed by two extravascular 7-0 monofilament stitches to avoid retraction. Consequently both ends were slid over a 5-mm balloon catheter introduced 3 cm downstream. The margins were manually positioned end-to-end after balloon inflation, then 2 cc BioGlue was applied and dried for 2 minutes. The distal elastic snares were removed and the anastomosis opened after 5 minutes. Once hemostasis was controlled, the incision was closed. After extubation, the dogs were kept in the recovery room for 4 hours. Analgesics were given as necessary. Finally, all medication given, the animal was returned to a controlled animal facility where the general health of the dog was checked daily. The Animal Experimentation Ethical Committee of the Ghent University approved all procedures. All animals received care conforming with the international and Belgian legislation ("Guide for the Care and Use of Laboratory Animals" [National Institutes of Health publication 85-23, revised 1985]).
Eight animals were randomly included into the study. All operative survivors underwent angiographic control after 6 weeks. If both anastomoses were found occluded, the animal was euthanized for pathologic examination. The rest of the animals underwent repeated angiography after 3 months. For histology by light microscopy the anastomotic site was transected longitudinally and embedded in paraffin; 4-mm thick sections were stained with hematoxylin and eosin, Masson's trichrome for collagen, Orcin for elastin, and myoperoxidase for granulocytes. Monoclonal antibodies (with cross-reactivity to canine origin) were used to detect macrophages (MAC-1, Serotec, Oxford, UK). Ultra-thin sections (60 nm) of the anastomosis were prepared for examination with a Zeiss EM 900 transmission electron microscope. Tissue specimens were embedded in Epon and stained with uranylacetate and lead citrate.
Meanwhile, BioGlue was submerged in vitro into a protease-1 enzymatic solution (Ventana, Phoenix, AZ) for up to 3 months. Glue lysate was separated on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis column and analyzed by mass spectrometry [3].
Clinical experience
Direct sutureless reanastomosis using BioGlue was performed in 16 iliac arteries. Average temporary arterial occlusion time was recorded 9.5 (±2.5) minutes. Seven dogs survived the first 6 weeks, although 1 needed intravenous support for several days. One animal died of excessive bleeding at the left anastomotic site on the first operative day.
Angiographic control
The 7 operative survivors underwent angiographic control 6 weeks after operation. Flow was assessed following the TIMI-protocol for coronary arteries. Eleven anastomoses were patent and three vessels were totally occluded. Perfect run-off (TIMI-flow 3) without signs of distal alteration of the circulation was recorded in nine vessels (Fig 1).
Two vessels presented vascular string formation downstream from the anastomotic site with poor visualization of the distal vascular bed in one specimen (TIMI 1). Dog 4 with both iliac arteries occluded was euthanized. Autopsy showed marked fungal infection signs at both suture lines probably due to perioperative contamination. The 6 survivors were reinvestigated another 6 weeks later. Angiography confirmed perfect patency of 7 anastomoses. In two vessels the flow deteriorated. All animals were euthanized for histologic examination. Table 1
summarizes operative and angiographic data and final outcome of all animals.
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From a histologic point of view, canine arteries contain a higher incidence of myocytes and less elastin in the media, making them more prone to spasm than human arteries. However, their structure decreases intimal hyperplastic response to arterial injury [4]. We already demonstrated the feasibility of coronary vascular anastomoses using BioGlue as the sole adhesive with an acceptable short-term patency in the dog model [5]. Several types of glue have been used in the past to secure an anastomosis, with disappointing results. Cyanoacrylic glues showed good tensile strength, but caused deterioration of the vascular wall and aneurysm formation [1]. Formaldehyde used in high concentration (37%) in the gelatin-resorcinol-formaldehyde glue seems to have a toxic effect on the medial wall, with necrosis of the smooth muscle cells and disruption of the media [6].
Our experimental canine study demonstrated that BioGlue produced a patent artery sutureless anastomosis in 57% of cases after 3 months. In contrast to the long-term goat studies conducted by Gundry and colleagues [7], we noticed an early and considerable inflammatory response. During the initial period granulocytes reactivity to the glue was predominant. In our canine model the glue was broken down by enzymatic reaction (confirmed by submerging the glue into a proteinase solution). Furthermore, the "lytic" glue remnants seem to disappear, scavenged by macrophages. The glue was steadily replaced by scar tissue (healing by secundam intentionam). In 7 cases smooth coverage of the intimal gap by fibroblastic tissue without intima proliferation or obstruction of the lumen was observed. Marked differences in endothelial lining with localized infiltration of elastin fibers into the intima were found in 28% of the specimens.
Hewitt and coworkers [8] detected only minimal and inconsistent inflammatory response in the sheep model. They also reported preliminary results of minimal reactions in humans 2 and 9 months after acute type A ascending aortic repair. By contrast, some studies have revealed adverse reactions to the glue such as the fibrosis and strictures found in piglets by Lemaire and coworkers [9], although whether the same reaction occurs in children is unknown. Experimental results should be reproducible, but reaction to the bovine glue seems minimal or absent in herbivores. In juvenile animals and omnivores (pig, dog) the onset of the inflammatory response is early and important. In our canine model the glue was definitively broken down. It is yet unknown to what substance. Nevertheless, the human being is more likely to react as an omnivore. Also, the possibility of an immunologic response to the glue or its remnants is to be considered, in analogy to a strong antibody response to serum bovine albumin noticed in 10% of previously vaccinated dogs [10]. BioGlue could act as an immunogen and carry the potential to sensitize patients to bovine products. This phenomenon was not investigated during our study.
The good results of recent clinical BioGlue studies, ongoing in Europe and the United States, should be confirmed by experimental series in an appropriate animal model. Before the glue can be considered as a true alternative to standard techniques, the exact early and late effect of the glue on human tissue remains to be investigated.
Disclosures and freedom of investigation
No financial conflict of interest exists with any commercial entity whose products are described, reviewed, evaluated or compared in the manuscript. We have freedom of investigation in all aspects of this work.
Footnotes
The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.
References
This article has been cited by other articles:
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  W. Schiller, H. Rudorf, C. B. Welzel, M. J. Kiderlen, C. Probst, O. Dewald, and A. Welz Sutureless anastomoses of rabbit carotid arteries with BioGlue. J. Thorac. Cardiovasc. Surg., December 1, 2007; 134(6): 1513 - 1518. [Abstract] [Full Text] [PDF]
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G. J. Van Nooten, P. Somers, R. Forsyth, K. Narine, Y. Van Belleghem, S. Jacobs, and F. De Somer Autologous glue: Part of the sticky mystery unraveled J. Thorac. Cardiovasc. Surg., August 1, 2007; 134(2): 415 - 423. [Abstract] [Full Text] [PDF]
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