Experimental use of crosslinked gelatin glue for arterial hemostasis in cardiovascular surgery

Abstract

BACKGROUND: Anastomotic needle hole bleeding is a frequently encountered problem in cardiovascular surgeries.

OBJECTIVE: To examine the feasibility of crosslinked gelatin glue as an anastomotic needle hole sealant in comparison with fibrin glue.

METHODS: The in vitro burst water pressures were measured for gelatin and fibrin glue sealed needle holes of expanded polytetrafluoroethylene (ePTFE) or collagen coated woven polyester grafts. For in vivo investigations, abdominal aorta-ePTFE graft anastomoses of heparinized beagle dogs were sealed by gelatin or fibrin glue and hemostatic efficacy was judged. The implanted sites were re-examined 4 weeks postoperatively.

RESULTS: The in vitro burst water pressures of gelatin glue sealed needle holes of both grafts were higher than those sealed by fibrin glue. For in vivo canine studies, hemostasis was successful for all gelatin glue applied suture lines, but not two out of three fibrin glue treated sites when 3-0 polypropylene suture was employed. Although adhesions of surrounding tissues were intense for all sites 4 weeks postoperatively, inflammation was more severe for the fibrin glue group compared to those of gelatin glue.

CONCLUSIONS: Gelatin glue was found to be an effective and safe sealant for accomplishing hemostasis of anastomotic needle holes of vascular grafts.

Keywords

Gelatin sealant fibrin glue needle hole hemostasis

1. Introduction

Cardiovascular operations are frequently performed with systemic heparinization that may contribute to intractable surgical bleeding. Prolonged bleeding is a significant clinical problem which can increase in operative time and patient morbidity [1]. However, it may be difficult to make some surgical repair in cases of bleeding from a deep surgical field, a weak field or a needle hole. Anastomotic needle hole bleeding can be an issue for all types of anastomoses, however, it is particularly so with expanded polytetrafluoroethylene (ePTFE) grafts sutured with polypropylene sutures that are commonly employed in these procedures. In such cases, manual compression with gauze, reversal of heparin, or topical hemostatic agents including surgical sealants has been used to manage bleeding.

Various types of commercially available hemostatic agents have been clinically investigated as needle hole sealants of ePTFE implants, including collagen, oxidized cellulose, gelatin, gelatin with thrombin, CoSeal^® surgical sealant (polyethylene glycol (PEG)-based product) (Baxter, Fremont, CA, USA) [2,3], gelatin–resorcinol–formaldehyde (GRF^®) glue (Cardial, Technopole, Sainte-Etienne, France) [4], absorbable cyanoacrylate [5] and fibrin glue. Among these, fibrin glue is the most commonly used sealant in these clinical situations. Clinical studies have demonstrated the effectiveness and safety of fibrin glue as an ePTFE needle hole sealant [6–11]. However, fibrin glue has a number of shortcomings, including virus transmission, low adhesive strength, troublesome preparation and high price. Other products also have disadvantages such as high tissue toxicity and postoperative wound complications for GRF^® glue, and high price for synthetic sealants. Hence, an effective and fast performing hemostatic agent which is easy to prepare, safe and cost-effective is required.

A crosslinked gelatin glue, which is composed of gelatin and glutaraldehyde (GA) aqueous solutions, has been developed as a surgical sealant and adhesion barrier [12]. Gelatin has very long history as an absorbable, non-toxic biomaterial, and its safety has been proven. GA has been used as crosslinking agents for several commercial surgical sealants such as Bioglue^® (bovine serum albumin with GA) (CryoLife, Inc., Kennesaw, GA, USA) and GRF^® glue. Previously, it was demonstrated that the in vitro water resistant pressure of a gelatin glue sealed needle hole on a ePTFE vascular graft was higher than that of fibrin glue [12]. In addition, for neurological applications, the gelatin glue was found to be an effective dural sealant to prevent cerebrospinal fluid leakage from suture holes [13]. In this study, the feasibility of gelatin glue as a sealant for anastomotic suture holes of vascular grafts was compared with that of fibrin glue by in vitro and in vivo canine model studies.

2. Material and methods

2.1. Materials

Gelatin (Medigelatin^®) which was extracted from the porcine skin to have an isoelectric point of 5.25 was supplied from Nippi Co. (Tokyo, Japan). GA solution (25%), phosphate-buffered saline (PBS(−)) and fetal bovine serum were purchased from Wako Pure Chemical Industries, Ltd (Osaka, Japan). Fibrin glue (Beriplast, CSL Behring) was purchased from Fuji Chemicals Ltd (Tokyo, Japan). All other reagents and surgical materials were purchased from Wakenyaku Co. Ltd (Osaka, Japan). Doubly distilled water was used for any preparation. Healthy female beagles (aged 11–13 months, weighing 9–11 kg) were purchased from Shimizu Laboratory Animal Supply Co. (Kyoto, Japan). This study was approved by the ethical committee meeting for animal research of Nara Medical University (Reference number: 10341), and animal housing, human care and surgical procedures were performed in accordance with its institutional guidelines. All surgical procedures in this study were performed by one cardiovascular surgeon under routine sterile conditions.

2.2. In vitro evaluation of sealing on pricked vascular graft

Expanded polytetrafluoroethylene (ePTFE) vascular graft (GORE-TEX Stretch Vascular Grafts, W.L. Gore & Associates, Flagstaff, AZ, USA) and collagen coated woven polyester graft (InterGard Woven Grafts, MAQUET GmbH & Co. KG) were cut into a circle with a diameter of 18 mm, immersed in fetal bovine serum (10 ml) and assembled into the apparatus for testing burst pressure, as illustrated in Fig. 1. A water leak hole was prepared by pricking the graft with a needle with a gauge size 23 which has a outer diameter of 0.64 mm. Gelatin (26 wt%), which was dissolved in PBS(−) at pH 7, and GA (1.5 wt%) aqueous solutions, packed individually into syringes, were preheated to 50°C and applied onto the needle hole using a joining connector and a disposable static mixer with rubbing by a finger at 37°C. The total volume of applied gel was 200 µl with the gelatin/GA volume ratio of 7.5/1.0. In the case of fibrin glue, 50 µl of fibrinogen solution was applied on the needle hole with rubbing, followed by spraying fibrinogen (50 µl) and thrombin (100 µl) solutions simultaneously using an application nozzle. Three minutes after the application, water pressure in the apparatus was gradually increased and the pressure was read with a pressure gauge (Valcom Co., Ltd, Osaka, Japan) when water leakage occurred.

Fig. 1.

Apparatus for testing sealing effect.

2.3. In vivo evaluation

Seven beagle dogs were divided randomly into gelatin and fibrin glue groups. First, pentobarbital (25 mg/kg) was applied to each dog by intravenous injection for general anesthesia. For preventing infection, we used Hibitane solution to disinfect the abdomen of dogs and equipment. All surgical instruments, gauze and embedding material were sterilized in advance. Operation was performed in an aseptic fashion. After the midline incision, the abdominal aorta (diameter = 4–5 mm) was exposed and heparin (80 unit/kg) was administered intravenously. After cutting off the blood flow by clamping two places of abdominal aorta with hemostatic forceps, 4 cm of aorta was resected. An anastomosis was made between the abdominal aorta and PTFE graft (diameter = 5 mm, length = 5 cm) using 3-0 ( $n = 3$ ), 4-0 ( $n = 2$ ) or 6-0 ( $n = 2$ ) polypropylene sutures (PROLENE^® polypropylene suture, ETHICON) in order to change the size of needle holes. After completion, hemostatic forceps were removed carefully to test blood leakage from the needle holes. Blood flow was cut off again and blood surrounding the anastomosis was carefully wiped off by gauze. For hemostasis, 200 µl of gelatin (experimental group) or fibrin glue (control group) was applied around the suture line by rubbing or rub-and-splay method, respectively, as described previously. The hemostatic forceps were removed 3 min after application of the glue and any hemorrhage was judged by the operating surgeons for 5 min. If bleeding was observed, more glue was applied after cutting off the blood flow. When sealing was completed, the abdomen was closed leaving the hemostatic agent on the abdominal aorta. The dogs were returned to the animal housing for recovery. All operations were performed by the same surgeon. Four weeks after the first operation, re-examination of the operation site was performed under anesthetic condition. The tissue adhesions at the anastomotic region were judged by the operating surgeons. After the dogs were euthanized by overdose of anesthesia (pentobarbital 250 mg/kg), the area was resected and soaked in formalin after rinsing with saline. The anastomotic regions were embedded in paraffin, cut and stained with hematoxylin and eosin for evaluation by a pathologist who was blinded to the treatment groups.

2.4. Statistical analysis

For the in vitro study, quantitative results were obtained from eight samples and the results were expressed as mean ± SD. Statistical analysis was carried out using unpaired Student’s t-test. A value of $p < 0.05$ was considered to be statistically significant.

3. Results

3.1. In vitro sealing efficiency on pricked vascular graft

The sealing effects of gelatin and fibrin glues on pricked ePTFE and collagen coated woven polyester vascular grafts were studied by measuring the maximal water pressure when water leakage occurred from the sealed hole. After setting the vascular graft, which was presoaked in fetal bovine serum, into the apparatus (Fig. 1), a water leak hole (expected size of 0.32 mm²) was prepared by pricking the graft with a 23 gauge needle. For gelatin glue, preheated gelatin and GA solutions (total of 200 µl) were applied simultaneously using a multi-element static mixer and were rubbed with a finger to let the glue to penetrate into the needle hole before complete gelation. Fibrin glue was applied by rub-and-spray method, which was by rubbing the 50 µl of fibrinogen solution onto the needle hole with a finger followed by spraying fibrinogen (50 µl) and thrombin (100 µl) solutions simultaneously using a spray nozzle. As shown in Fig. 2, the burst water pressures of gelatin and fibrin glue sealed needle holes on ePTFE vascular grafts were 470 ± 74 and 360 ± 139 mmHg, respectively ( $p = 0.08$ ). In the case of polyester grafts, the burst water pressure of gelatin glue sealed hole (176 ± 61 mmHg) was significantly higher than that of fibrin glue (112 ± 37 mmHg) ( $p < 0.05$ ).

Fig. 2.

Burst water pressures of gelatin and fibrin glue sealed pricked ePTFE and collagen-coated woven polyester vascular grafts ( $n = 8$ , ^∗ $p < 0.05$ ).

3.2. In vivo hemostatic efficiency

To investigate hemostatic efficacy of glues on anastomotic needle holes, ePTFE vascular grafts were implanted between abdominal aortas of heparinized beagle dogs using different sizes of polypropylene sutures and suture lines were sealed by gelatin or fibrin glue after confirmation of needle hole bleeding. Bleeding status of needle holes created by 3-0, 4-0 and 6-0 polypropylene sutures were spurting, fast flow and oozing, respectively. Figure 3 shows photographs of (A) an abdominal aorta, (B) performing anastomosis with an ePTFE graft, (C) after applications of gelatin and (D) fibrin glues at the anastomotic sites. Hemostatic efficacy, which was defined as absence of any detectable bleeding, was judged by the operating surgeons for 5 min. Table 1 shows results of hemostasis of gelatin and fibrin glues (by showing the numbers of unsuccessful bleeding cases). Gelatin glue stopped bleeding from all sizes of needle holes effectively. On the other hand, fibrin glue stopped bleeding from the needle holes of 4-0 and 6-0 polypropylene sutured anastomotic sites, but bleeding occurred for two out of three sites sutured with 3-0 polypropylene immediately after clumps were released. Extra glue was applied for hemostasis in the case of bleeding. All seven dogs survived the surgical procedure and the wounds were well healed.

3.3. In vivo tissue reactivity

Figure 4 shows photographs of surgical sites treated with (A) gelatin and (B) fibrin glues 4 weeks after the surgery. From gross observations, all animals had thick fibrosis over the anastomotic sites as well as all areas of ePTFE grafts. The extents of adhesions at the anastomotic sites where glues were applied

Table 1
Number of bleeding cases at aorta-ePTFE graft anastomotic sites after sealing with 200 µl of gelatin or fibrin glue

Suture size	3-0 ( $n = 3$ )	4-0 ( $n = 2$ )	6-0 ( $n = 2$ )
Gelatin glue	0	0	0
Fibrin glue	2	0	0

Fig. 3.

Perioperative photographs of (A) an abdominal aorta of a beagle dog, (B) performing anastomosis of aorta-ePTFE graft, (C) after applications of gelatin and (D) fibrin glues at the anastomotic sites. (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151534.)

Fig. 4.

Photographs of 6-0 polypropylene sutured aorta-ePTFE anastomotic sites treated with (A) gelatin and (B) fibrin glues 4 weeks postoperatively. (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151534.)

were moderate and severe for gelatin and fibrin glues, respectively. All operation sites were not associated with noticeable inflammatory exudates. Both gelatin and fibrin glues were not detected at the sites. Figure 5 shows representative histological images of anastomotic regions treated with (A)–(B) gelatin or (C)–(D) fibrin glue 4 weeks postoperatively. Only focal and mild inflammatory cell infiltration, mainly composed of lymphocytes, was shown in the adhered tissues for gelatin glue treated anastomotic regions. On the other hand, infiltration, mainly composed of neutrophils and proliferation of neovascular vessels were evident for adhered tissues on the fibrin glue sealed anastomotic sites. Microscopic examinations also did not identify any residual gelatin and fibrin glues, indicating total degradation of these glues within 4 weeks in vivo.

Fig. 5.

Histological examination for 6-0 polypropylene sutured aorta-ePTFE graft anastomotic regions treated with (A)–(B) gelatin or (C)–(D) fibrin glue 4 weeks postoperatively. (A), (C) showing adhered tissues on top of the ePTFE vascular graft (original magnification: ×4); (B), (D) showing high resolutions of adhered tissues (original magnification: (B) ×20, (D) ×40). (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151534.)

4. Discussion

Fibrin glue is based on the natural clotting system, and consists of two component systems; one contains human fibrinogen, Factor XIII, fibronectin, and fibrinolysis inhibitor, while the other contains human thrombin and calcium chloride. When two solutions are mixed, fibrin molecules, which were converted from fibrinogen by thrombin, assemble into a fibrin clot and are stabilised by the thrombin-activated factor XIII. The clotting process only takes less than 30 seconds. Fibrin glue has been clinically used for controlling bleeding in cardiovascular surgery for more than 30 years [14] and successfully applied in many other surgical fields [14–16]. Fibrin glue has also been routinely used as a needle hole sealant for vascular graft anastomoses. Despite the successful application of fibrin glue, one of disadvantages is its low adhesive strength. Many technical efforts have been made to improve its adhesive strength, and these application methods include separate dripping method using two individual syringes, simultaneous dripping method using a joining connector and a cannula, spray method using a spray application nozzle and rub-and-spray method. The rub-and-spray method consists of rubbing the fibrinogen solution onto needle holes with a finger followed by spraying both the fibrinogen and thrombin solutions using a spray nozzle. This method has been reported to have the strongest sealing and hemostatic effects among four methods mentioned above [17], and clinically proven to be extremely effective for hemostasis of needle holes [18]. The rub-and-spray has become a standard method to apply fibrin glue for hemostasis in cardiovascular surgery in our institute, and hence, was employed in this study.

Gelatin glue used in this study is consisting of gelatin and GA aqueous solutions. Previous study demonstrated that in vitro water resistant pressure of a gelatin glue sealed needle hole on ePTFE vascular graft was significantly increased upon rubbing [12]. Hence, this application technique was used for gelatin glue for the in vitro and in vivo canine model studies. The burst water pressures of gelatin glue sealed pricked needle holes on ePTFE and collagen-coated woven polyester grafts were higher than those of fibrin glue, but only significantly different for polyester grafts. For both glues, the burst water pressers on polyester grafts were less than half of those on ePTFE, possibly due to higher wettability of the former graft than the latter when presoaked in fetal bovine serum to mimic the in vivo environment. Dry condition is generally recommended when the glue is applied, however complete dryness is not always possible in surgical situations. The higher adhesive strength of gelatin glue than fibrin glue can be explained by their unique molecular characteristics, as previously described [12]. Gelatin is present in solution mostly as random chains that create the conspicuous chain entanglement in the gel form leading to strong adhesions, whereas this is very difficult for fibrillar protein molecules like fibrinogen. In addition, the high viscosity of gelatin solution makes it less dripping and easier to apply to sloped organs.

To investigate the efficacy of gelatin glue as an anastomotic needle hole sealant, ePTFE grafts were implanted between aortas of heparinized beagle dogs. While fine sutures are used for anastomoses of grafts in general operative situations, to test the capability of gelatin and fibrin glues, we artificially made different sizes of needle holes by using three sizes of polypropylene sutures. The 3-0, 4-0 and 6-0 sutures created spurting, fast flow and oozing types of bleeding, respectively. Gelatin glue successfully stopped bleeding from all sizes of needle holes. On the other hand, immediate bleeding occurred for two out of three fibrin glue sealed 3-0 sutured needle holes when clumps were released. This is in agreement with the in vitro study which showed that the gelatin glue can withstand higher water pressure than the fibrin glue.

Crosslinked gelatin films have been investigated for use as anti-adhesive materials [19–21]. Gelatin, which is a denatured collagen, is physiologically very inactive, and its film is bioinert, hydrophilic and mechanically strong that make it suitable as an anti-adhesive barrier. The previous study has demonstrated the effectiveness of gelatin glue for preventing tissue adhesions using the rat cecum abrasion model [12]. As a dura mater sealant, the extent of adhesion formed between the dura mater and the adjacent bone was significantly less in the gelatin glue applied group compared to the control group without any sealants [13]. In the present study, intense tissue adhesion was present not only at the anastomotic sites but also the entire area of ePTFE vascular grafts in all treated animals. Nonetheless, the extent of adhesion at the anastomotic sites was less severe in the gelatin glue treated group compared to that of the fibrin glue.

Although the use of GA, which is potentially toxic, is the most concern for the gelatin glue, a multi-element static mixer is used to mix two solutions well to eliminate the possibility of applying high concentration of GA solution directly to the tissues. Because of high reactivity between GA and gelatin in the well-mixed solution, the concentration of free GA in the glue seems statistically very low. In addition, GA in neutral aqueous solutions is present in the equilibrate state with polymerized forms, which is expected to have lower cytotoxicity than its monomer. The previous study has demonstrated the lower cytotoxicity of the gel extract than that of free GA when compared at the same concentrations of aldehydes [12]. Additionally, the concentration of aldehydes in gelatin glue is much lower than that of commercially available products, such as Bioglue^® and GRF^®. Previous in vivo studies have shown that local inflammation was minimal when gelatin glue was applied on rat cecum [12] and there were no complications when it was used as dura mater sealants in rat and canine models [13,22]. This study demonstrated that gelatin glue did not cause any adverse tissue reactions or anastomotic complications in canine aorta-ePTFE graft models 4 weeks postoperatively.

Some of the limitations of this study are as follow. Firstly, for the in vivo animal study, the number of anastomotic sites studied in each group was relatively small, and greater numbers are required to provide statistically significant differences. Secondly, the in vivo tissue reactivity of gelatin glue was only evaluated up to four weeks, and long-term investigations are necessary to fully examine its safety. Finally, this study only compared gelatin glue with fibrin glue, and hence comparison with other commercially available hemostatic agents would help to evaluate the effectiveness of the newly developed gelatin glue.

5. Conclusion

Gelatin glue appears to be a highly effective needle hole sealant when used at aorta-ePTFE anastomoses in a canine model. Our short-term in vivo results suggest that this glue does not cause any adverse tissue reaction or anastomotic complications. Although gelatin glue did not prevent adhesion of surrounding tissues to anastomotic sites, the extent of adhesion was less severe than that of fibrin glue. In addition, histological examinations of gelatin treated anastomotic sites showed less inflammation compared to those treated with fibrin glue. Long-term in vivo studies are required to further investigate the safety of gelatin glue for use in clinical setting.

Conflict of interest

The authors have no conflict of interest.

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Experimental use of crosslinked gelatin glue for arterial hemostasis in cardiovascular surgery

Abstract

Keywords

1. Introduction

2. Material and methods

2.1. Materials

2.2. In vitro evaluation of sealing on pricked vascular graft

2.4. Statistical analysis

3. Results

3.1. In vitro sealing efficiency on pricked vascular graft

3.3. In vivo tissue reactivity

Table 1 Number of bleeding cases at aorta-ePTFE graft anastomotic sites after sealing with 200 µl of gelatin or fibrin glue

5. Conclusion

Conflict of interest

References

Table 1
Number of bleeding cases at aorta-ePTFE graft anastomotic sites after sealing with 200 µl of gelatin or fibrin glue