Surg Today DOI 10.1007/s00595-013-0777-0
ORIGINAL ARTICLE
Adhesive strength of ethyl-2-cyanoacrylate tissue adhesive: how strong is it? Shih-Han Hung • Te-Ming Tseng • Hsin-Te Hsu How Tseng
•
Received: 6 January 2013 / Accepted: 1 April 2013 Ó Springer Japan 2013
Abstract Purpose We evaluated the adhesive strength of ethyl-2cyanoacrylate and compared the findings with those of traditional monofilament synthetic sutures. We also investigated the factors that could affect the effectiveness of cyanoacrylate bonding by skin surface modifications at the adhesion site. Methods Using a porcine skin model, we measured the maximum load for ethyl-2-cyanoacrylate adhesive under various application conditions. Results When the application width was 5 mm, no differences were found in the maximum force load for one layer or two layers of ethyl-2-cyanoacrylate adhesive (3.3 ± 1.7 and 4.8 ± 1.5 N, p = 0.176). When the application width was extended to 10 mm, the maximum force load for one layer was 8.2 ± 0.6 N, which was significantly higher than for
5 mm (p \ 0.002). The force fell to within the loads generated by 6-0 to 5-0 ETHILONTM monofilament non-absorbable synthetic sutures. Roughening of the application surface had little effect on adhesion; however, smoothing resulted in a decrease in overall adhesive strength. Conclusions The width of the application of ethyl-2cyanoacrylate adhesive over the skin defect was important for achieving good and stable adhesive strength. Increasing the number of layers of adhesive through repeated applications of the cyanoacrylate did not increase overall adhesive strength. Skin surface modifications other than regular cleaning should be avoided. Keywords Ethyl-2-cyanoacrylate Suture Adhesive strength
Introduction S.-H. Hung T.-M. Tseng H.-T. Hsu Department of Otolaryngology, Taipei Medical University Hospital, Taipei, Taiwan S.-H. Hung H. Tseng Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan S.-H. Hung H.-T. Hsu Department of Otolaryngology, School of Medicine, Taipei Medical University Hospital, Taipei, Taiwan H. Tseng Department of Biochemistry, School of Medicine, Taipei Medical University, Taipei, Taiwan H. Tseng (&) Department of Otolaryngology, Head and Neck Surgery, Taipei Medical University Hospital, No. 252, Wu-Hsing Street, Taipei 110, Taiwan e-mail: [email protected]
Sutures have played an essential role in surgery for thousands of years. Various materials have been used including natural materials made from plants (flax, hemp, and cotton) and animal hair, tendons, arteries, muscle strips and nerves, silk, and gut. With advances in the chemical industry, synthetic absorbable and non-absorbable materials became available in the 20th century. The recent development of topical cyanoacrylates has gained much attention due to their potential use in surgical wound adhesion and closure [1, 2]. The applications of cyanoacrylates have been further expanded to include repair of the ventricular wall, wound closure in prosthetic vascular graft surgery, adhesion of dental materials to bone, repair of the larynx and peripheral nerves, endoscopic sealing of a pancreatic fistula, and even in anastomosis of the intestine [3–11]. Besides its use as adhesives, more recently the cyanoacrylate was further used in the control of bleeding [12, 13].
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In addition to the ease of its application and lack of sutures, cyanoacrylate adhesives have been reported to be highly biocompatible even when used in neural, thoracic and cardiac surgery [14–16]. Some studies have even reported that ethylcyanoacrylate has bacteriostatic and bactericidal action in vitro [17, 18]. The ease of application of cyanoacrylates promotes the use of modern materials, especially in the field of nerve regeneration, by decreasing local inflammatory responses caused by traditional stitch sutures [19]. One of the most important questions raised about the use of cyanoacrylates as a wound adhesive is: ‘‘How strong is it?’’ The binding strength of sutures or adhesive materials is vital to prevent wound breakdown, which could result in bleeding, infections, and other related complications. Moreover, it is crucial for clinicians to understand the most effective or efficient way of applying the cyanoacrylate tissue adhesive. We conducted this study to evaluate the adhesive strength of ethyl-2-cyanoacrylate in a porcine skin model and compare the results with those of traditional monofilament synthetic sutures. Furthermore, we investigated the factors that could affect the effectiveness of cyanoacrylate bonding by skin surface modifications at the adhesion site.
Materials and methods Standard suture materials and cyanoacrylate tissue adhesives
group, each strip was sutured with only one stitch using the sizes of ETHILONTM sutures mentioned above. In the cyanoacrylate group, the glue was applied according to the manufacturer’s instructions. This group was further classified into three different subgroups according to the width of glue application and the number of layers as follows: 5 mm application width on each side in one layer; 5 mm on each side in double layers; and 10 mm on each side in a single layer. After each application of the cyanoacrylate layer, the strips were allowed to air-dry at room temperature for at least 10 min. The reattached skin strips were then loaded onto an Instron servo hydraulic machine (8501M, Instron, Canton, MA, USA) for mechanical tests. The device was set to the ‘‘pull to break’’ mode with a pre-tension of 10 N and an elongation speed of 1 mm per second. The tension-elongation curves were recorded until breaking point when the maximal tension load of the suture/adhesion had been reached (Fig. 1). Histology of the adhesive interface of porcine skin and ethyl-2-cyanoacrylate Ethyl-2-cyanoacrylate was applied to the porcine skin and allowed to dry in room air for 30 min. The skin with cyanoacrylate was then cut into small blocks for further histological examinations. Tissue blocks were sectioned after being frozen at -80 °C. Adjacent sections were stained with hematoxylin and eosin (H&E) (Sigma, USA) before observations.
Four different diameters of monofilament non-absorbable synthetic suture materials (U.S.P. size 3-0; 4-0; 5-0 & 6-0) (ETHILONTM, ETHICON, USA) were used to test the material strength. The diameters of these sutures were 0.2, 0.15, 0.1, and 0.07 mm, respectively. These sutures were selected as the reference standards, because ETHILONTM sutures are commonly used in closure of the skin in various wounds. Ethyl-2-cyanoacrylate was used as the wound adhesive and supplied in the product form of EpigluÒ (Meyer-Haake GmbH Medical Innovations, Germany).
Adhesive surface modifications for the evaluation of cyanoacrylate adhesion
Mechanical strength measurement with a porcine skin model
The data from each group were compared using the Student’s t test. A p value of \0.05 was considered to indicate significance.
After being obtained freshly from a local supplier, porcine skin was washed with detergents to remove excessive grease. The skin was then cut into 1.0 9 15.0 cm rectangular strips, about 5 mm thick including the epidermis, dermis, and the subcutaneous fat layer. After marking the midline, each strip was cut in half along the marked incision line. These two pieces were then sutured or glued back together along the incision line prior to biomechanical testing. The free ends of the sutures were tied with instrument ties including three half-hitches. All of the knots were tied by one experienced surgeon. In the suture
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We assessed the effect of modifications to the surface of the skin strips on adhesion strength. Modifications included smoothing the surface with sand paper and scrubbing cream, and creating multiple dimples with spike needles to increase the roughness of the adhesion surface. Statistical methods
Results Maximum load for standard suture materials The maximum force loads for the 3-0, 4-0, 5-0, and 6-0 monofilament non-absorbable synthetic sutures were 30.1 ± 2.8, 20.8 ± 2.3, 13.2 ± 0.1, and 4.5 ± 0.1 N, respectively (Fig. 2).
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Fig. 1 The reattached skin straps were loaded for mechanical tests (8501 M, Instron, Canton, MA, USA). The tension-elongation curves were recorded until the breaking point under maximal tension load of the suture/adhesion had been reached
acrylate adhesive were 3.3 ± 1.7 and 4.8 ± 1.5 N, respectively, without a significant difference between the groups (p = 0.176). In the group with an application width of 10 mm in a single layer, the maximum force load was 8.2 ± 0.6 N, which was significantly higher than that in the 5 mm groups (p \ 0.002; Fig. 3). Testing of the 10 mm single layer group was repeated another three times for consistency. The maximum force load was remarkably inconsistent throughout different independent experiments (Table 1). In every independent experiment, the skin samples were collected from the same animal; however, the animal skin used and the experiment environments between these experiments were not identical. Fig. 2 The maximum force load for 3-0, 4-0, 5-0, and 6-0 ETHILONTM monofilament non-absorbable synthetic sutures
Maximum load for the ethyl-2-cyanoacrylate adhesive with different application widths and layers When the application width was 5 mm, the maximum force loads for one layer and two layers of the ethyl-2-cyano-
Histology of the adhesive interface of the porcine skin and ethyl-2-cyanoacrylate Under H&E staining, the cyanoacrylate was clearly seen and appeared to be a uniform transparent layer. The skin layer and the cyanoacrylate layer were closely tethered and even interlaced. There did not seem to be any gaps between these two distinct layers (Fig. 4).
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Fig. 3 Maximum load for ethyl-2-cyanoacrylate adhesive under different application widths and layers (*p \ 0.05)
Fig. 4 Histology of the adhesive interface of the porcine skin and ethyl-2-cyanoacrylate (H&E 9400) (*ethyl-2-cyanoacrylate layer, arrow interface between the skin and the cyanoacrylate layer)
Table 1 The maximum force load for a single layer of 10 mm wide ethyl-2-cyanoacrylate adhesive was remarkably inconsistent throughout different independent experiments Independent experiment
1
2
3
4
Maximum force load (N)
8.2 ± 0.6
10.3 ± 2.0
15.2 ± 2.3
21.1 ± 1.4
In every independent experiment, skin samples were collected from the same animal. However, the animal skin used and the experiment environments between these experiments were not identical. Inconsistency of the maximum load for ethyl-2-cyanoacrylate adhesives (10 mm single layer)
Effect of adhesive surface modification on cyanoacrylate adhesion The maximum force load for the application width of 10 mm in a single layer group applied to the skin surface modified with spike needles did not significantly differ from that of the unmodified group (15.6 ± 5.2 vs. 15.2 ± 2.3 N; p = 0.883). However, when the skin surface was modified with sand paper and scrubbing cream, the maximum force load decreased significantly to 7.0 ± 2.5 N (p = 0.0006; Fig. 5).
Discussion The results of this study showed that when the application width of the ethyl-2-cyanoacrylate adhesive was 10 mm, the maximum force load for a single layer fell within the loads generated by 6-0 to 5-0 ETHILONTM monofilament non-absorbable synthetic sutures stitched at an interval of 1 cm. Interestingly, the manufacturer’s technical guide
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Fig. 5 The maximum force load for a single layer of 10 mm wide ethyl-2-cyanoacrylate adhesive applied to the skin surface with different modifications (*p \ 0.05)
does not specify the recommended application width and gives no clear information or instructions about the application width of the cyanoacrylate. Bruns et al. [20] recommended that at least three layers be applied to ensure optimal strength for wound closure. However, there seems to be of little evidence supporting this statement. Thus, in most cases we were unsure about the optimal way of applying these adhesives in relation to how widely and in how many layers it should be applied. Our data provide useful clinical information to help clinicians decide when and where ethyl-2-cyanoacrylate should be used for wound closure. Techniques of suturing for closing cutaneous wounds have evolved over thousands of years. Although the materials and techniques have changed, the goals remain
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the same: closing dead spaces, supporting and strengthening wounds until healing increases their tensile strength, approximating skin edges for an esthetically pleasing and functional result, and minimizing the risks of bleeding and infection [21, 22]. Depending on the types of laceration or defect, appropriate suture materials are chosen in an attempt to achieve adequate wound closure. The currently available wound closure materials include sutures, skin adhesives, strips, energy-based devices, staples, and ligating clips. Ideal suture materials should have the following characteristics: good handling characteristics, minimal tissue reaction, allow for secure knots, adequate tensile strength, not cut through tissues, ability to be sterilized with ease, be non-electrolytic, be non-allergenic, and be cost effective [23]. Incorrect selection of wound closure material may lead to undesirable results and complications such as premature wound rupture, bleeding, and infections. In our study, the adhesive strength of ethyl-2-cyanoacrylate was proven to be equivalent to that of 5–0 ETHILONTM monofilament. As 5–0 ETHILONTM monofilament is frequently used for the face, nose, ears, eyebrows, and eyelids, our findings suggest that ethyl-2-cyanoacrylate may serve as an ideal alternative wound closing material. The advantages of applying ethyl-2-cyanoacrylate for wound closure in these areas are that it reduces the risk of accidental needle punctures, excludes the need for suture removal, and there are no concerns of wound dehiscence from insecure knots. Discovered by Ardis in 1949, the most studied cyanoacrylate families are methyl (R = CH3), ethyl (R = C2H5), butyl and isobutyl (R = C4H9), and octyl (R = C8H17) [24–26]. These cyanoacrylates are usually prepared in liquid form until application into water-containing environments. Most commercially available tissue adhesives are based on ethyl-cyanoacrylate, which has a smaller lateral chain than the other surgical adhesives. This increases its adhesive strength and results in a shorter healing time [24, 26]. Immediately after exposure to water, ethyl-2-cyanoacrylate rapidly polymerizes and forms a polymer layer that bonds to the underlying surface. This not only allows the material to penetrate into irregular surfaces and promote strong adhesion, but also makes its application possible on wet surfaces [24, 26]. The water absorption properties of cyanoacrylates also make it possible to use in controlling needle hole bleeding and even epistaxis [25, 27]. We examined the binding surface between the cyanoacrylate and the skin surface in histological sections. Surprisingly, we found that the skin and cyanoacrylate seemed to interlace into each other. Since cyanoacrylate is an acrylic resin that rapidly polymerizes in the presence of water, it is also known as a water-activated bonding material [28]. While this water-absorbing bonding process
has not shown significant advantages over conventional composite resins as an orthodontic adhesive, this property seemed to contribute to the formation of the interlacing adhesion layers in the present study. Although further studies are needed to validate our findings, we suspect that all of the water between the skin and the applied cyanoacrylate is absorbed during the polymerization process, thus causing the skin layer to be tightly bonded to the cyanoacrylate layer. This interlaced adhesion seemed to form a tight ‘‘grip’’ on the attached surfaces, accounting for most of the strength of the cyanoacrylate adhesive. This may further explain why roughening the surface did not increase the bonding strength over a clean skin surface. Conversely, smoothing the skin surface by scrubbing may have disrupted this gripping effect, causing the adhesion to break under smaller loads. The limitation of this study lies in the fact that the results were based on a porcine skin model. The textures of human and porcine skin are different, and this may have contributed to different adhesive properties when the ethyl2-cyanoacrylate was applied. However, Kong et al. [29] found that porcine skin resembles human skin and is likely to be useful for studying diffusion dynamics of materials in human skin. Thus, it is reasonable to assume that similar results will be obtained when cyanoacrylate is tested on human skin. Moreover, during our experiments, we noted very little variation between skin blocks from the same pig, but that the maximum force load differed among different pigs (data not shown). This implies that the adhesion force for ethyl-2-cyanoacrylate may differ slightly between individuals. We attribute this inconsistency to the different texture and moisture properties of different porcine skins. As different experiment sections were carried out independently, experiment conditions such as room temperature and moisture may also have been different. Although the consistency of cyanoacrylate adhesive forces was not the main focus of this study, the inconsistent data also reveal the possible ranges of adhesive strength; however, these differences were still clinically acceptable and did not seem important enough to affect the decision to choose ethyl-2-cyanoacrylate for skin wound closure. Unfortunately, we were not able to develop any surface modification protocols to increase the bonding strength of ethyl-2-cyanoacrylate. Further studies are needed to establish optimal adhesion conditions for cyanoacrylates. Based on the findings of the present study, we recommend the following: 1.
2.
Before the application of ethyl-2-cyanoacrylate, the skin surfaces should be prepared only with thorough cleaning and gentle washing. When applying ethyl-2-cyanoacrylate, the application should be at least 1 cm wide.
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3.
Applying multiple layers of ethyl-2-cyanoacrylate may increase its water-proofing or antibacterial properties, but it will not increase the overall adhesion strength.
In conclusion, the application width of the ethyl-2-cyanoacrylate adhesive over the skin defect was crucial for achieving good and stable adhesive strength. Increasing the number of layers of adhesive did not increase the overall adhesive strength. Roughening the application surface seemed to have little effect on adhesion; however, smoothing led to a decrease in overall adhesive strength. Skin surface modifications other than regular cleaning should be avoided. Acknowledgments This work was supported by the Taipei Medical University Hospital Research Fund (101TMUH-NE-04). The ethyl-2cyanoacrylate tissue adhesive (EpigluÒ) used in this study was kindly provided by Meyer-Haake GmbH Medical Innovations (Germany). This study was supported by the Taipei Medical University Hospital Research Fund (101TMUH-NE-04). There are no other financial disclosures related to this study. Conflict of interest conflicts of interest.
Prof. How Tseng and his co-authors have no
References 1. Shapiro AJ, Dinsmore RC, North JH Jr. Tensile strength of wound closure with cyanoacrylate glue. Am Surg. 2001;67: 1113–5. 2. Hallock GG. Expanded applications for octyl-2-cyanoacrylate as a tissue adhesive. Ann Plast Surg. 2001;46:185–9. 3. Totaro P, Minzioni G. Patch-and-glue technique for left ventricular free wall rupture. Ann Thor Surg. 2002;74:294–5. 4. Maurer P, Bekes K, Gernhardt CR, Schaller HG, Schubert J. Tensile bond strength of different adhesive systems between bone and composite compared: an in vitro study. J Craniomaxillofac Surg. 2004;32:85–9. 5. Landegren T, Risling M, Brage A, Persson JK. Long-term results of peripheral nerve repair: a comparison of nerve anastomosis with ethyl-cyanoacrylate and epineural sutures. Scand J Plast Reconstr Surg Hand Surg. 2006;40:65–72. 6. Sofuni A, Itoi T, Tsuchiya T, Itokawa F, Kurihara T, Moriyasu F, et al. Endoscopic sealing of a pancreatic fistula using ethyl-2cyanoacrylate. Endoscopy. 2006;38(Suppl 2):E71–2. 7. Elemen L, Sarimurat N, Ayik B, Aydin S, Uzun H. Is the use of cyanoacrylate in intestinal anastomosis a good and reliable alternative? J Pediatr Surg. 2009;44:581–6. 8. Lyons MB, Lyons GD, Webster D, Wheeler VR. Adhesives in larynx repair. Laryngoscope. 1989;99:376–81. 9. Aksoy M, Turnadere E, Ayalp K, Kayabali M, Ertugrul B, Bilgic L. Cyanoacrylate for wound closure in prosthetic vascular graft surgery to prevent infections through contamination. Surg Today. 2006;36:52–6. 10. Tebala GD, Ceriati F, Ceriati E, Vecchioli A, Nori S. The use of cyanoacrylate tissue adhesive in high-risk intestinal anastomoses. Surg Today. 1995;25:1069–72. 11. Takenaka H, Esato K, Ohara M, Zempo N. Sutureless anastomosis of blood vessels using cyanoacrylate adhesives. Surg Today. 1992;22:46–54.
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12. Chen Y, Chen F, Xie P, Qiu P, Zhou J, Deng Y. Combined oxidized cellulose and cyanoacrylate glue in the management of severe presacral bleeding. Surg Today. 2009;39:1016–7. 13. Muradi A, Yamaguchi M, Sakamoto N, Okada T, Idoguchi K, Sugimoto K. Successful n-butyl cyanoacrylate embolization of a spontaneous rupture of the internal mammary artery in a patient with myelodysplastic syndrome: report of a case. Surgery Today 2012. 14. de Azevedo CL, Marques MM, Bombana AC. Cytotoxic effects of cyanoacrylates used as retrograde filling materials: an in vitro analysis. Pesquisa odontologica brasileira. Braz Oral Res. 2003;17:113–8. 15. Kaplan M, Bozkurt S, Kut MS, Kullu S, Demirtas MM. Histopathological effects of ethyl 2-cyanoacrylate tissue adhesive following surgical application: an experimental study. Eur J Cardiothorac Surg. 2004;25:167–72. 16. Rickett T, Li J, Patel M, Sun W, Leung G, Shi R. Ethyl-cyanoacrylate is acutely nontoxic and provides sufficient bond strength for anastomosis of peripheral nerves. J Biomed Mater Res Part A. 2009;90:750–4. 17. de Almeida Manzano RP, Naufal SC, Hida RY, Guarnieri LO, Nishiwaki-Dantas MC. Antibacterial analysis in vitro of ethylcyanoacrylate against ocular pathogens. Cornea. 2006;25:350–1. 18. Romero IL, Malta JB, Silva CB, Mimica LM, Soong KH, Hida RY. Antibacterial properties of cyanoacrylate tissue adhesive: does the polymerization reaction play a role? Indian J Ophthalmol. 2009;57:341–4. 19. Merolli A, Marceddu S, Rocchi L, Catalano F. In vivo study of ethyl-2-cyanoacrylate applied in direct contact with nerves regenerating in a novel nerve-guide. J Mater Sci Mater Med. 2010;21:1979–87. 20. Bruns TB, Worthington JM. Using tissue adhesive for wound repair: a practical guide to dermabond. Am Fam Physician. 2000;61:1383–8. 21. Hochberg J, Meyer KM, Marion MD. Suture choice and other methods of skin closure. Surg Clin North Am. 2009;89:627–41. 22. Mackeen AD, Berghella V, Larsen ML. Techniques and materials for skin closure in caesarean section. Cochrane Database Syst Rev. 2012;9:CD003577. 23. Kudur MH, Pai SB, Sripathi H, Prabhu S. Sutures and suturing techniques in skin closure. Indian J Dermatol Venereol Leprol. 2009;75:425–34. 24. Shermak MA, Wong L, Inoue N, Crain BJ, Im MJ, Chao EY, et al. Fixation of the craniofacial skeleton with butyl-2-cyanoacrylate and its effects on histotoxicity and healing. Plast Reconstr Surg. 1998;102:309–18. 25. Toriumi DM, Raslan WF, Friedman M, Tardy ME. Histotoxicity of cyanoacrylate tissue adhesives. A comparative study. Arch Otolaryngol Head Neck Surg. 1990;116:546–50. 26. Weber SC, Chapman MW. Adhesives in orthopaedic surgery. A review of the literature and in vitro bonding strengths of bonebonding agents. Clinical orthopaedics and related research 1984:249–261. 27. Singer AJ, McClain SA, Katz A. A porcine epistaxis model: hemostatic effects of octylcyanoacrylate. Otolaryngol Head Neck Surg. 2004;130:553–7. 28. Karamouzos A, Mavropoulos A, Athanasiou AE, Kolokithas G. In vivo evaluation of a moisture-activated orthodontic adhesive: a comparative clinical trial. Orthod Craniofac Res. 2002;5:170–8. 29. Kong R, Bhargava R. Characterization of porcine skin as a model for human skin studies using infrared spectroscopic imaging. Analyst. 2011;136:2359–66.
ORIGINAL ARTICLE
Adhesive strength of ethyl-2-cyanoacrylate tissue adhesive: how strong is it? Shih-Han Hung • Te-Ming Tseng • Hsin-Te Hsu How Tseng
•
Received: 6 January 2013 / Accepted: 1 April 2013 Ó Springer Japan 2013
Abstract Purpose We evaluated the adhesive strength of ethyl-2cyanoacrylate and compared the findings with those of traditional monofilament synthetic sutures. We also investigated the factors that could affect the effectiveness of cyanoacrylate bonding by skin surface modifications at the adhesion site. Methods Using a porcine skin model, we measured the maximum load for ethyl-2-cyanoacrylate adhesive under various application conditions. Results When the application width was 5 mm, no differences were found in the maximum force load for one layer or two layers of ethyl-2-cyanoacrylate adhesive (3.3 ± 1.7 and 4.8 ± 1.5 N, p = 0.176). When the application width was extended to 10 mm, the maximum force load for one layer was 8.2 ± 0.6 N, which was significantly higher than for
5 mm (p \ 0.002). The force fell to within the loads generated by 6-0 to 5-0 ETHILONTM monofilament non-absorbable synthetic sutures. Roughening of the application surface had little effect on adhesion; however, smoothing resulted in a decrease in overall adhesive strength. Conclusions The width of the application of ethyl-2cyanoacrylate adhesive over the skin defect was important for achieving good and stable adhesive strength. Increasing the number of layers of adhesive through repeated applications of the cyanoacrylate did not increase overall adhesive strength. Skin surface modifications other than regular cleaning should be avoided. Keywords Ethyl-2-cyanoacrylate Suture Adhesive strength
Introduction S.-H. Hung T.-M. Tseng H.-T. Hsu Department of Otolaryngology, Taipei Medical University Hospital, Taipei, Taiwan S.-H. Hung H. Tseng Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan S.-H. Hung H.-T. Hsu Department of Otolaryngology, School of Medicine, Taipei Medical University Hospital, Taipei, Taiwan H. Tseng Department of Biochemistry, School of Medicine, Taipei Medical University, Taipei, Taiwan H. Tseng (&) Department of Otolaryngology, Head and Neck Surgery, Taipei Medical University Hospital, No. 252, Wu-Hsing Street, Taipei 110, Taiwan e-mail: [email protected]
Sutures have played an essential role in surgery for thousands of years. Various materials have been used including natural materials made from plants (flax, hemp, and cotton) and animal hair, tendons, arteries, muscle strips and nerves, silk, and gut. With advances in the chemical industry, synthetic absorbable and non-absorbable materials became available in the 20th century. The recent development of topical cyanoacrylates has gained much attention due to their potential use in surgical wound adhesion and closure [1, 2]. The applications of cyanoacrylates have been further expanded to include repair of the ventricular wall, wound closure in prosthetic vascular graft surgery, adhesion of dental materials to bone, repair of the larynx and peripheral nerves, endoscopic sealing of a pancreatic fistula, and even in anastomosis of the intestine [3–11]. Besides its use as adhesives, more recently the cyanoacrylate was further used in the control of bleeding [12, 13].
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In addition to the ease of its application and lack of sutures, cyanoacrylate adhesives have been reported to be highly biocompatible even when used in neural, thoracic and cardiac surgery [14–16]. Some studies have even reported that ethylcyanoacrylate has bacteriostatic and bactericidal action in vitro [17, 18]. The ease of application of cyanoacrylates promotes the use of modern materials, especially in the field of nerve regeneration, by decreasing local inflammatory responses caused by traditional stitch sutures [19]. One of the most important questions raised about the use of cyanoacrylates as a wound adhesive is: ‘‘How strong is it?’’ The binding strength of sutures or adhesive materials is vital to prevent wound breakdown, which could result in bleeding, infections, and other related complications. Moreover, it is crucial for clinicians to understand the most effective or efficient way of applying the cyanoacrylate tissue adhesive. We conducted this study to evaluate the adhesive strength of ethyl-2-cyanoacrylate in a porcine skin model and compare the results with those of traditional monofilament synthetic sutures. Furthermore, we investigated the factors that could affect the effectiveness of cyanoacrylate bonding by skin surface modifications at the adhesion site.
Materials and methods Standard suture materials and cyanoacrylate tissue adhesives
group, each strip was sutured with only one stitch using the sizes of ETHILONTM sutures mentioned above. In the cyanoacrylate group, the glue was applied according to the manufacturer’s instructions. This group was further classified into three different subgroups according to the width of glue application and the number of layers as follows: 5 mm application width on each side in one layer; 5 mm on each side in double layers; and 10 mm on each side in a single layer. After each application of the cyanoacrylate layer, the strips were allowed to air-dry at room temperature for at least 10 min. The reattached skin strips were then loaded onto an Instron servo hydraulic machine (8501M, Instron, Canton, MA, USA) for mechanical tests. The device was set to the ‘‘pull to break’’ mode with a pre-tension of 10 N and an elongation speed of 1 mm per second. The tension-elongation curves were recorded until breaking point when the maximal tension load of the suture/adhesion had been reached (Fig. 1). Histology of the adhesive interface of porcine skin and ethyl-2-cyanoacrylate Ethyl-2-cyanoacrylate was applied to the porcine skin and allowed to dry in room air for 30 min. The skin with cyanoacrylate was then cut into small blocks for further histological examinations. Tissue blocks were sectioned after being frozen at -80 °C. Adjacent sections were stained with hematoxylin and eosin (H&E) (Sigma, USA) before observations.
Four different diameters of monofilament non-absorbable synthetic suture materials (U.S.P. size 3-0; 4-0; 5-0 & 6-0) (ETHILONTM, ETHICON, USA) were used to test the material strength. The diameters of these sutures were 0.2, 0.15, 0.1, and 0.07 mm, respectively. These sutures were selected as the reference standards, because ETHILONTM sutures are commonly used in closure of the skin in various wounds. Ethyl-2-cyanoacrylate was used as the wound adhesive and supplied in the product form of EpigluÒ (Meyer-Haake GmbH Medical Innovations, Germany).
Adhesive surface modifications for the evaluation of cyanoacrylate adhesion
Mechanical strength measurement with a porcine skin model
The data from each group were compared using the Student’s t test. A p value of \0.05 was considered to indicate significance.
After being obtained freshly from a local supplier, porcine skin was washed with detergents to remove excessive grease. The skin was then cut into 1.0 9 15.0 cm rectangular strips, about 5 mm thick including the epidermis, dermis, and the subcutaneous fat layer. After marking the midline, each strip was cut in half along the marked incision line. These two pieces were then sutured or glued back together along the incision line prior to biomechanical testing. The free ends of the sutures were tied with instrument ties including three half-hitches. All of the knots were tied by one experienced surgeon. In the suture
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We assessed the effect of modifications to the surface of the skin strips on adhesion strength. Modifications included smoothing the surface with sand paper and scrubbing cream, and creating multiple dimples with spike needles to increase the roughness of the adhesion surface. Statistical methods
Results Maximum load for standard suture materials The maximum force loads for the 3-0, 4-0, 5-0, and 6-0 monofilament non-absorbable synthetic sutures were 30.1 ± 2.8, 20.8 ± 2.3, 13.2 ± 0.1, and 4.5 ± 0.1 N, respectively (Fig. 2).
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Fig. 1 The reattached skin straps were loaded for mechanical tests (8501 M, Instron, Canton, MA, USA). The tension-elongation curves were recorded until the breaking point under maximal tension load of the suture/adhesion had been reached
acrylate adhesive were 3.3 ± 1.7 and 4.8 ± 1.5 N, respectively, without a significant difference between the groups (p = 0.176). In the group with an application width of 10 mm in a single layer, the maximum force load was 8.2 ± 0.6 N, which was significantly higher than that in the 5 mm groups (p \ 0.002; Fig. 3). Testing of the 10 mm single layer group was repeated another three times for consistency. The maximum force load was remarkably inconsistent throughout different independent experiments (Table 1). In every independent experiment, the skin samples were collected from the same animal; however, the animal skin used and the experiment environments between these experiments were not identical. Fig. 2 The maximum force load for 3-0, 4-0, 5-0, and 6-0 ETHILONTM monofilament non-absorbable synthetic sutures
Maximum load for the ethyl-2-cyanoacrylate adhesive with different application widths and layers When the application width was 5 mm, the maximum force loads for one layer and two layers of the ethyl-2-cyano-
Histology of the adhesive interface of the porcine skin and ethyl-2-cyanoacrylate Under H&E staining, the cyanoacrylate was clearly seen and appeared to be a uniform transparent layer. The skin layer and the cyanoacrylate layer were closely tethered and even interlaced. There did not seem to be any gaps between these two distinct layers (Fig. 4).
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Fig. 3 Maximum load for ethyl-2-cyanoacrylate adhesive under different application widths and layers (*p \ 0.05)
Fig. 4 Histology of the adhesive interface of the porcine skin and ethyl-2-cyanoacrylate (H&E 9400) (*ethyl-2-cyanoacrylate layer, arrow interface between the skin and the cyanoacrylate layer)
Table 1 The maximum force load for a single layer of 10 mm wide ethyl-2-cyanoacrylate adhesive was remarkably inconsistent throughout different independent experiments Independent experiment
1
2
3
4
Maximum force load (N)
8.2 ± 0.6
10.3 ± 2.0
15.2 ± 2.3
21.1 ± 1.4
In every independent experiment, skin samples were collected from the same animal. However, the animal skin used and the experiment environments between these experiments were not identical. Inconsistency of the maximum load for ethyl-2-cyanoacrylate adhesives (10 mm single layer)
Effect of adhesive surface modification on cyanoacrylate adhesion The maximum force load for the application width of 10 mm in a single layer group applied to the skin surface modified with spike needles did not significantly differ from that of the unmodified group (15.6 ± 5.2 vs. 15.2 ± 2.3 N; p = 0.883). However, when the skin surface was modified with sand paper and scrubbing cream, the maximum force load decreased significantly to 7.0 ± 2.5 N (p = 0.0006; Fig. 5).
Discussion The results of this study showed that when the application width of the ethyl-2-cyanoacrylate adhesive was 10 mm, the maximum force load for a single layer fell within the loads generated by 6-0 to 5-0 ETHILONTM monofilament non-absorbable synthetic sutures stitched at an interval of 1 cm. Interestingly, the manufacturer’s technical guide
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Fig. 5 The maximum force load for a single layer of 10 mm wide ethyl-2-cyanoacrylate adhesive applied to the skin surface with different modifications (*p \ 0.05)
does not specify the recommended application width and gives no clear information or instructions about the application width of the cyanoacrylate. Bruns et al. [20] recommended that at least three layers be applied to ensure optimal strength for wound closure. However, there seems to be of little evidence supporting this statement. Thus, in most cases we were unsure about the optimal way of applying these adhesives in relation to how widely and in how many layers it should be applied. Our data provide useful clinical information to help clinicians decide when and where ethyl-2-cyanoacrylate should be used for wound closure. Techniques of suturing for closing cutaneous wounds have evolved over thousands of years. Although the materials and techniques have changed, the goals remain
Surg Today
the same: closing dead spaces, supporting and strengthening wounds until healing increases their tensile strength, approximating skin edges for an esthetically pleasing and functional result, and minimizing the risks of bleeding and infection [21, 22]. Depending on the types of laceration or defect, appropriate suture materials are chosen in an attempt to achieve adequate wound closure. The currently available wound closure materials include sutures, skin adhesives, strips, energy-based devices, staples, and ligating clips. Ideal suture materials should have the following characteristics: good handling characteristics, minimal tissue reaction, allow for secure knots, adequate tensile strength, not cut through tissues, ability to be sterilized with ease, be non-electrolytic, be non-allergenic, and be cost effective [23]. Incorrect selection of wound closure material may lead to undesirable results and complications such as premature wound rupture, bleeding, and infections. In our study, the adhesive strength of ethyl-2-cyanoacrylate was proven to be equivalent to that of 5–0 ETHILONTM monofilament. As 5–0 ETHILONTM monofilament is frequently used for the face, nose, ears, eyebrows, and eyelids, our findings suggest that ethyl-2-cyanoacrylate may serve as an ideal alternative wound closing material. The advantages of applying ethyl-2-cyanoacrylate for wound closure in these areas are that it reduces the risk of accidental needle punctures, excludes the need for suture removal, and there are no concerns of wound dehiscence from insecure knots. Discovered by Ardis in 1949, the most studied cyanoacrylate families are methyl (R = CH3), ethyl (R = C2H5), butyl and isobutyl (R = C4H9), and octyl (R = C8H17) [24–26]. These cyanoacrylates are usually prepared in liquid form until application into water-containing environments. Most commercially available tissue adhesives are based on ethyl-cyanoacrylate, which has a smaller lateral chain than the other surgical adhesives. This increases its adhesive strength and results in a shorter healing time [24, 26]. Immediately after exposure to water, ethyl-2-cyanoacrylate rapidly polymerizes and forms a polymer layer that bonds to the underlying surface. This not only allows the material to penetrate into irregular surfaces and promote strong adhesion, but also makes its application possible on wet surfaces [24, 26]. The water absorption properties of cyanoacrylates also make it possible to use in controlling needle hole bleeding and even epistaxis [25, 27]. We examined the binding surface between the cyanoacrylate and the skin surface in histological sections. Surprisingly, we found that the skin and cyanoacrylate seemed to interlace into each other. Since cyanoacrylate is an acrylic resin that rapidly polymerizes in the presence of water, it is also known as a water-activated bonding material [28]. While this water-absorbing bonding process
has not shown significant advantages over conventional composite resins as an orthodontic adhesive, this property seemed to contribute to the formation of the interlacing adhesion layers in the present study. Although further studies are needed to validate our findings, we suspect that all of the water between the skin and the applied cyanoacrylate is absorbed during the polymerization process, thus causing the skin layer to be tightly bonded to the cyanoacrylate layer. This interlaced adhesion seemed to form a tight ‘‘grip’’ on the attached surfaces, accounting for most of the strength of the cyanoacrylate adhesive. This may further explain why roughening the surface did not increase the bonding strength over a clean skin surface. Conversely, smoothing the skin surface by scrubbing may have disrupted this gripping effect, causing the adhesion to break under smaller loads. The limitation of this study lies in the fact that the results were based on a porcine skin model. The textures of human and porcine skin are different, and this may have contributed to different adhesive properties when the ethyl2-cyanoacrylate was applied. However, Kong et al. [29] found that porcine skin resembles human skin and is likely to be useful for studying diffusion dynamics of materials in human skin. Thus, it is reasonable to assume that similar results will be obtained when cyanoacrylate is tested on human skin. Moreover, during our experiments, we noted very little variation between skin blocks from the same pig, but that the maximum force load differed among different pigs (data not shown). This implies that the adhesion force for ethyl-2-cyanoacrylate may differ slightly between individuals. We attribute this inconsistency to the different texture and moisture properties of different porcine skins. As different experiment sections were carried out independently, experiment conditions such as room temperature and moisture may also have been different. Although the consistency of cyanoacrylate adhesive forces was not the main focus of this study, the inconsistent data also reveal the possible ranges of adhesive strength; however, these differences were still clinically acceptable and did not seem important enough to affect the decision to choose ethyl-2-cyanoacrylate for skin wound closure. Unfortunately, we were not able to develop any surface modification protocols to increase the bonding strength of ethyl-2-cyanoacrylate. Further studies are needed to establish optimal adhesion conditions for cyanoacrylates. Based on the findings of the present study, we recommend the following: 1.
2.
Before the application of ethyl-2-cyanoacrylate, the skin surfaces should be prepared only with thorough cleaning and gentle washing. When applying ethyl-2-cyanoacrylate, the application should be at least 1 cm wide.
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Surg Today
3.
Applying multiple layers of ethyl-2-cyanoacrylate may increase its water-proofing or antibacterial properties, but it will not increase the overall adhesion strength.
In conclusion, the application width of the ethyl-2-cyanoacrylate adhesive over the skin defect was crucial for achieving good and stable adhesive strength. Increasing the number of layers of adhesive did not increase the overall adhesive strength. Roughening the application surface seemed to have little effect on adhesion; however, smoothing led to a decrease in overall adhesive strength. Skin surface modifications other than regular cleaning should be avoided. Acknowledgments This work was supported by the Taipei Medical University Hospital Research Fund (101TMUH-NE-04). The ethyl-2cyanoacrylate tissue adhesive (EpigluÒ) used in this study was kindly provided by Meyer-Haake GmbH Medical Innovations (Germany). This study was supported by the Taipei Medical University Hospital Research Fund (101TMUH-NE-04). There are no other financial disclosures related to this study. Conflict of interest conflicts of interest.
Prof. How Tseng and his co-authors have no
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