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Department of Surgery, University of California at San Francisco Medical Center (UCSF) and San Francisco Veterans Affairs Medical Center (SFVAMC), San Francisco, California
Accepted for publication December 22, 2008.
* Address correspondence to Dr Tseng, Division of Cardiothoracic Surgery, UCSF Medical Center, 500 Parnassus Ave, Suite 405W, Box 0118, San Francisco, CA 94143-0118 (Email: elaine.tseng{at}ucsfmedctr.org).
| Abstract |
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Methods: Samples of BioGlue (CryoLife, Inc, Kennesaw, GA), CoSeal (Baxter Healthcare International, Palo Alto, CA), Tisseel (Baxter Healthcare Corp, Glendale, CA), and Crosseal (OMRIX Biopharmaceuticals, Inc, New York, NY) sealants underwent biaxial tensile testing. A Hookean strain energy function was fit to the stress-strain response of each sample, and the Young's modulus was obtained for comparison of material stiffness.
Results: Sealants demonstrate a relatively linear response to loading; mean elastic moduli for BioGlue (3,122.04 ± 1,639.68 kPa), CoSeal (100.02 ± 67.60 kPa), Tisseel (102.59 ± 41.13 kPa), and Crosseal (53.56 ± 32.59 kPa) varied greatly. CoSeal and Tisseel have no significant difference in stiffness (p = 0.897) while Crosseal is more compliant than Tisseel (p = 0.004) and CoSeal (p = 0.055). BioGlue is stiffer than CoSeal, Tisseel, and Crosseal (p < 0.001). Furthermore, BioGlue is much stiffer than cited properties of Dacron grafts, glutaraldehyde-fixed porcine roots, and human aortic tissue. However, CoSeal and Tisseel are much more compliant than the aortic root conduits.
Conclusions: BioGlue is much less compliant than the other sealants studied and materials available for aortic root replacement. A surgeon's choice of glue should be determined by stiffness as well as sealant efficacy. Sealants with greater stiffness than aortic root replacement material may restrict normal physiologic dilation and cause anastomotic strictures.
| Introduction |
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Tisseel and Crosseal are fibrin sealants formed from concentrated fibrinogen and thrombin, whose biochemical reaction has been well-delineated [3]. They differ in their purification process and constituent antifibrinolytic agents [4]. Contrary to fibrin sealants, CoSeal and BioGlue are independent of the coagulation cascade and use cross-linking agents to covalently bind to tissue surfaces. Adhesion is based on the presence of a matrix and a cross-linking agent. The matrix is an inert synthetic polymer or a protein that subsequently becomes functionalized. CoSeal is a completely synthetic sealing agent consisting of two different tetrafunctional polyethylene glycol macromers, while BioGlue is a biologic protein matrix, consisting of 10% glutaraldehyde and a 45% bovine serum albumin solution [5, 6].
Although studies have evaluated adhesives with respect to hemostatic efficacy, biocompatibility, and safety, few have studied the mechanical properties of surgical glues [7, 8]. Mechanical properties play a significant role in cardiovascular applications when the sealant is subjected to cyclic loads, such as on the ventricle or arterial tree. When several materials work together they absorb the loads to which the structure is subjected. Each material differentially absorbs load based on its mechanical behavior, resulting in different internal stresses and deformations for each material. A mismatch of mechanical properties may result in shearing effects produced every cycle and generate excess stresses in the tissue. The goal of this study was to determine the mechanical properties of four common commercial glues utilized in cardiovascular surgery (Tisseel, Crosseal, CoSeal, and BioGlue) and compare the results to known properties of aortic root replacements.
| Material and Methods |
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Both BioGlue and CoSeal were applied as liquids that polymerize rapidly to hydrogel, which has high water content and readily releases water. The human body in general is a form of hydrogel, with an average water content of 70%. These two products will remain flexible and pliable while hydrated inside the human body. However, if they are left exposed to the environment (air) for a long period they will desiccate and harden, resulting in breakdown [10]. Therefore, all of the glue samples were kept hydrated and soaked in normal saline while in the stretcher.
Data Collection and Analysis
Samples were tested using equibiaxial displacement controlled protocols; encoders located at the end of each linear arm of the stretcher recorded arm movement to ensure equal and simultaneous deformation. The same experimental protocol in the same order was repeated for each specimen. Specimens were stretched equibiaxially to a maximum strain of 10%. Glue samples that did not tear during the stretching protocol were analyzed: n = 8, Tisseel; n = 5, Crosseal; n = 8, CoSeal; n = 6, BioGlue. Analysis of stress, the average amount of force exerted per unit area, and strain assumes material incompressibility. The deformation gradient (F) was calculated for each recorded point of the loading cycle. The five markers within the strain region formed four nonoverlapping triangles (Fig 1). Green strain was calculated for each triangle independently to assess homogeneity of deformation and the data from the four triangles were subsequently averaged. Components of Green strain in the two directions were calculated using the following equations:
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x and
y (
i = L
i/L
i0, i = x, y) are stretches in the x and y directions (Fig 1). Planar forces (fx, fy) during deformation were converted to Cauchy stresses in the principal directions and given by
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The stiffness of a material is its overall resistance to deformation under an applied load. This reflects the mechanical properties of the material as well as its shape, size, and loading conditions. In order to compare surgical glues we chose to evaluate the modulus of elasticity, or Young's modulus, a mathematic description of the material's tendency to deform when a force is applied. This measurement is defined as the slope of the stress-strain curve. The modulus of elasticity provides a normalized comparison of the four types of glue, accounting for variation in the size and thickness of individual samples. Stress-strain data were fit to a linear Hookean function, and Young's modulus was determined to reflect stiffness of the glues. One way analysis of variance was performed to test for differences between surgical glues. Reported values are quoted as mean ± standard deviation and statistical analyses were performed using MATLAB (v 7.0).
Material Properties of Aortic Root Replacement Conduits
Mechanical properties of Dacron grafts, glutaraldehyde-fixed porcine roots, and human aortic homografts have been obtained from literature. Mechanical properties of unused, woven, double-velour vascular graft (Boston Scientific, Medi-tech division, Natick, MA) was determined using a biaxial tensile system [11]. Stress-strain relationships in the circumferential and axial direction up to 30% strain were obtained. Comparison with our data was conducted using the maximum stiffness of Dacron samples by the largest slope of the stress-strain diagram. Zhou and colleagues [12] investigated mechanical properties of porcine roots fixed with 0.625% glutaraldehyde using ring specimens. A mathematical model for a flexible circular ring was used to determine the mean Young's modulus, which was used as comparison with our data. With regard to the human ascending aorta, Choudhury and colleagues [13] used a biaxial tensile tester system to evaluate the mechanical properties of the tissue. The average stress-strain curves demonstrated a nonlinear viscoelastic response and reported stiffness in both low and high stress regions; the high stress stiffness was used for comparison with our data.
| Results |
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| Comment |
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Hemostatic Efficacy
Surgical glues are commonly used as standard adjuncts in cardiovascular surgery. Substantial evidence has shown that adhesives have a positive impact on surgical results by shortening operative time and reducing perioperative bleeding [14–16]. Selection of a particular glue depends on hemostatic efficacy, availability, cost, ease of use and preparation, tissue cellular response, effects on wound healing, and likelihood of transmission of blood-borne diseases [17]. Tisseel and Crosseal are fibrin agents utilized to seal vascular anastomoses in both arterial and venous blood vessels. CoSeal is used in vascular reconstructions to achieve adjunctive hemostasis by mechanically sealing areas of leakage, especially suture lines. BioGlue is utilized as an adjunct to standard methods to achieve hemostasis in adult patients in open surgical repairs of large vessels. Applications of BioGlue in cardiovascular surgery include acute type A dissections, aortic root reconstruction, and left ventricular apical cannulation [18].
The adhesive strength of the four surgical glues has not been studied specifically in aortic root replacement. However, Cortes and colleagues [19] studied adhesive strength of the surgical glues using ex vivo human fetal membranes. Tisseel, CoSeal, and BioGlue were placed on punctured fetal membranes fastened to a pressure-controlled pump. Leak pressure of the membrane was measured and compared with a two-layer membrane system without sealant as control. Tisseel provided some sealing capabilities compared with control (46 ± 10 vs 27 ± 3 cm H2O). However, CoSeal and BioGlue achieved statistically significant higher average leak pressures compared with controls (CoSeal, 85 ± 11 cm H2O; and BioGlue, 78 ± 9 cm H2O; p < 0.05 for both). The leak pressures obtained suggested an inherent weak adhesive strength of fibrin glues, but a high adherence of CoSeal and BioGlue.
Clinical effectiveness of BioGlue as a surgical adjunct in cardiac and vascular surgical repairs was evaluated in a prospective, multicenter, randomized, controlled trial involving 151 patients [20]. Patients were randomized to receive standard surgical repair with BioGlue applied to the anastomotic site prior to clamp removal or standard surgical anastomotic repair alone, including use of pledgets, make-up stitches, hemostatic devices, thrombin glues, fibrin glues, and antifibrinolytic agents. Surgical procedures in this trial included cardiac, aortic, and peripheral vascular operations. Immediate anastomotic hemostasis was found to be superior with BioGlue compared with standard surgery controls (81% vs 57%; p < 0.003). Overall, BioGlue demonstrates hemostatic efficacy and adhesive strength, but is significantly stiffer than other glues and aortic root conduits.
In another study [21], hemostatic efficacy of CoSeal was examined in a prospective, randomized, controlled multicenter trial with 148 patients. Half of the patients were treated with CoSeal and the other half with a control of absorbable gelatin sponge and thrombin hemostat. The most common surgical procedures involved were infrainguinal revascularization and dialysis access shunts. Overall, subjects treated with CoSeal achieved immediate sealing at more than twice the rate of subjects treated with Gelfoam (Pharmacia & Upjohn Company. Division of Pfizer Inc, NY, NY)/thrombin (47% vs 20%; p < 0.001). Unlike BioGlue, CoSeal not only demonstrates hemostatic efficacy and adhesive strength but also is much more compliant than aortic root replacement materials.
BioGlue-Associated Complications
Sealants with greater stiffness than aortic root replacement materials may restrict normal physiologic dilation and cause anastomotic strictures [22]. In a study applying BioGlue to aortic anastomoses in 4-week-old piglets [22], BioGlue animals developed a 34% stenosis of aortic lumen area after 7 weeks of growth. Given the hemostatic efficacy and adhesive properties of BioGlue, the amount of glue applied should be minimized while achieving adequate results. BioGlue is commonly used in acute type A aortic dissections to reinforce the sinus segment and obliterate the false lumen [23]. Use of BioGlue in the aortic sinus significantly stiffens the repaired aortic root and alters wall stresses within the sinuses, which may have secondary effects on the leaflet stresses and durability [24].
Fibrin sealants have also been described for reconstruction of the aortic sinus in acute type A aortic dissection [25–28]. Because fibrin sealants and human aortic tissue have comparable stiffness, use of fibrin sealants instead of BioGlue may not restrict the normal physiologic dilation. However, fibrin glue alone may yield low adhesive strength. Due to this concern, an alternative method was proposed to reinforce the dissected aorta using fibrin glue and a neomedia fabric sheet [25]. The effect of fibrin glue and neomedia fabric on the composite material property of the dissected aortic root is unknown. Low early and late mortality, as well as low reoperation rate, has been reported for this technique [26].
BioGlue has also been associated with pseudoaneurysm development [20, 29]. When large quantities of BioGlue have been used, the surrounding tissue has been noted to be soft and friable [30]. Histology revealed retardation of normal healing, a local inflammatory process, and occasionally necrosis up to 2 years of BioGlue application [30]. BioGlue toxicity has been implicated in these changes in structural integrity [31]. However, the high stiffness of BioGlue as demonstrated in this study may result in an elevated wall stress, which could additionally weaken the tissue and predispose to late pseudoaneurysm formation.
Biodegradability
Biodegradability is critical to the long-term effects of surgical glues. Tisseel and Crosseal are biodegradable and adsorb in the body between 3 and 4 weeks after usage [32]. Long-term effects of fibrin sealants and their metabolites are minimal and there are no recent reports of significant fibrosis or tissue reaction using these materials. BioGlue and CoSeal are also both degradable after implantation; however, their degradation rates and mechanisms are different. CoSeal is resorbed by hydrolysis and reportedly degraded within less than 30 days of implantation. It could not be discerned grossly or histologically at 30 days [33]. However, BioGlue is resorbed slowly in the body by proteolysis and histologically the material was detectable after 1 year in a goat model [34]. For aortic root replacements, enhanced biodegradability would be considered a favorable aspect for surgical glues.
Study Limitations
Mechanical properties of aortic root replacement materials were not directly assessed in our experimental system. Instead, cited values of stiffness of Dacron grafts, glutaraldehyde-fixed porcine roots, and human aortic tissue were used for comparison [11–13]. Because the Young's modulus was used to reflect material stiffness, a comparison between the cited values and our results is valid.
We report a large standard deviation in the mean modulus of elasticity, indicating considerable variability in glue stiffness. This finding is mainly due to an inability to completely remove air traps in the samples during preparation. Although significant care was taken to avoid air trapping, this inhomogeneity is certainly present during surgical application as well. Therefore, the data reflect the variability of mechanical properties seen clinically. Air bubbles may result in an anisotropic behavior of the glue samples and lower the stiffness and bonding capabilities of the adhesives.
Conclusions and Future Research
A surgeon's choice of glue should be determined by stiffness in addition to other factors. We demonstrated that all the studied glues have a linear elastic response to tensile stress. BioGlue is significantly stiffer than CoSeal and the fibrin sealants. Furthermore, BioGlue is a much stiffer material than aortic root replacement conduits. Unlike BioGlue, CoSeal and Tisseel have similar elastic moduli, are more compliant than human aortic homografts, and are significantly more compliant than the fixed porcine roots and Dacron grafts.
Use of surgical glues as a substitute for sutures in aortic root replacements requires long-term stability and is not yet advocated. Properties required by appropriate glues for applications of sutureless anastomoses include adequate tensile strength and mechanical stability over time. The current bonding strength of available glues is likely not sufficient. However, the elastic behavior of surgical glues is in harmony with that of soft tissue and encourages further research to provide greater elasticity, not present in sutured tissue.
| Acknowledgments |
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