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An overview of surgical sealants

Leo H-H Cheng and Mustansir Alibhai
9 August, 2012  
Leo H-H Cheng
LLM MBChB BDS FRCS FDSRCS FRCS(OMFS) FHEA
Consultant Oral, Maxillofacial, 
Head and Neck Surgeon,
St Bartholomew’s
The Royal London and Homerton,
University Hospitals,
London, UK
Mustansir Alibhai
MBBS BDS MRCS MFDS
Specialist Registrar,
Oral, Maxillofacial, Head and Neck Surgery, St Bartholomew’s and the Royal London Hospitals,
London, UK
The drive to develop and produce surgical sealants is obvious, given the vast array of products and the rate at which new products appear on the market.
Mechanical methods of closure such as sutures, staples and clips are considered the gold standard for tissue repair. However, in certain circumstances these methods may not be suitable for closure, or may interfere with tissue function or the surgeon may wish to augment mechanical closure.(1)
Sealants are products used, particularly by surgeons, to repair tissue damaged by injury or surgery. Damaged tissues include skin, internal organs and blood vessels. Sealants are used to help reduce blood loss or prevent leaks and can be used in conjunction with mechanical methods such as sutures and staples. 
In this brief review the word sealant will encompass adhesives, glues and haemostats. 
Although subtle differences separate the products, often in surgical practice the terms are used interchangeably. However for completeness:
  • Sealants are absorbable materials used primarily to control internal bleeding and to seal tissue; they can prevent leaks of fluid and/or gas from a surgical incision
  • Surgical glues and adhesives are used to attach organs, structures or tissues to one other to effect repair. These materials can be enhanced by incorporating additional haemostatic or sealant properties.
Fibrin sealants
Fibrin sealant technology started after the production of concentrated fibrinogen in the 1960s. Its widespread use in Europe did not occur in the United States until the FDA approved the first fibrin sealant in 1989.(2)
In the same year, a clinical trial of fibrin sealant versus conventional topical haemostatic agents in reoperative cardiac surgery or emergency sternotomy revealed a significantly faster control of bleeding and decreased postoperative blood loss.(3)
Fibrin sealants usually comprise two components – fibrinogen and thrombin – and essentially mimic the final stages of the human coagulation pathway. The components interact during application to form a stable clot composed of fibrin. The mechanical strength of the fibrin sealant is mainly determined by the concentration of fibrinogen whereas the thrombin concentration determines the speed of clot formation.(2) Studies have also shown that adding aprotinin in the fibrin glue, which inhibits human trypsin and plasmin, may also increase the stability of the clot against lysis.(4)
Fibrin sealants are commonly used for many surgical procedures. The key indications for use are haemostasis and tissue sealing. They are used by surgeons for haemostasis in cardiac surgery, liver surgery and after splenic trauma.(5–7) Fibrin sealants have been used for reducing the frequency of pancreatic fistulas, but the results have been disappointing.(8) They have also been used as an aid to breast surgery to enhance adherence of skin flaps to the chest wall. Another postulated use is to aid skin-flap adherence following neck surgery. However, a recent meta-analysis concluded that fibrin sealants offered no advantage for this application over conventional surgical methods.(9)
Optimal application requires a dry operative field, which is often difficult to achieve, and thus fibrin sealants are usually used prophylactically while the suture line is dry to prevent possible haemorrhage.
Complications can arise because of potential viral or prion infection and patient sensitivity to bovine thrombin. This was the reason that deterred the FDA from initial approval of fibrin sealants.(10,11)
When wounds are closed in vivo by a fibrin sealant, a few sutures are usually implemented to reinforce the repair. Fibrin glues lack sufficient adhesive strength without the support of sutures or staples.(12)
Cyanoacrylates
Cyanoacrylates are substances initially developed commercially for use in products, such as Super Glue. They are liquid monomers that form polymers in the presence of water and quickly bind surfaces together. Therefore, they do not depend on evaporation to bond but become sticky with a small amount of moisture. 
Cyanoacrylates form toxic byproducts on degradation that can cause tissue inflammation and delay wound healing.(2) This led to the development of slower degrading cyanoacrylates that limit the development of toxic byproducts.
At present their main surgical use is in closing skin incisions, typically without sutures, but sometimes in combination with subcutaneous sutures. A randomised trial comparing 2-octylcyanoacrylate with subcuticular suturing for closure of surgical incisions after herniotomies in children showed no wound infection or dehiscence in any of the patients.(13) Despite this, subcuticular sutures are still preferred by many surgeons for skin closure as they usually guarantee no tissue dehiscence and a better wound cosmesis than cyanoacrylate glue.(14) 
Its use is best limited to the closure of small wounds, lacerations, and surgical incisions, as long as wound approximation can be achieved without undue tension. 
Thrombin and gelatin/thrombin mixtures 
Thrombin is a naturally derived enzyme involved in cell signalling, inflammation and the coagulation cascade. Activation of the intrinsic and extrinsic clotting pathways cleaves prothrombin to thrombin, which in turn converts fibrinogen to fibrin – the final pathway of the coagulation cascade.  
Until recently, the only commercially available stand-alone thrombin was derived from bovine plasma. Bovine-derived thrombin has potent biological activity to convert fibrinogen to fibrin, activate platelets and induce vascular contraction. However, it has also been shown to induce a strong immune response following human exposure.(15) Plasma-derived human thrombin and recombinant human thrombin are now available and were found to have similar efficacy and considerably less immunological response than bovine thrombin.(16)
A combination of bovine gelatin and pooled human thrombin has been developed as a flowable topical haemostatic agent, Floseal. Whenever the material comes in contact with blood, it starts sticking where there is fibrinogen. It does not stick to other surfaces so pressure can be applied on top of the product on a bleeding surface. This product has wide applications, is relatively easy to use and can help control bleeding in relatively inaccessible sites. This agent is relatively non-toxic and can be used on delicate structures, such as nerves.(17)
Polyethylene glycols
Polyethylene glycol polymers are synthetic hydrogels that have become popular tissue sealants. They can induce rapid cross-linking with inherent proteins, such as collagen, to form a matrix that adheres strongly to the applied tissue. A major advantage is the rapid sealing ability of the hydrogel and it does not require any human blood products or bovine components to inhibit bleeding. 
One concern with certain polyethylene glycol hydrogels is that, due to their affinity for water, the cross-linked gels swell within the body and must therefore be used sparingly in confined spaces. Thus, they should not be used to surround anatomical structures that could be harmed by compression. 
Although not biological haemostats, polyethylene glycols are also used as haemostatic agents for vascular and cardiac surgery applications in which swelling and expansion are not concerns. Their anastomotic sealing performance is equivalent to that of other biologically based sealants, but their main advantage lies in the speed with which they achieve haemostats.(2)
Albumin and glutaraldehyde tissue adhesive
Albumin and glutaraldehyde tissue adhesive is advocated for haemostasis of large blood vessels. It is a two-component sealant comprising glutaraldehyde and purified bovine albumin. The glutaraldehyde covalently cross-links the bovine serum albumin molecules to each other and to the tissue proteins at the wound site. This creates a tough scaffold that acts as a mechanical seal independent of the body’s clotting cascade.
This glutaraldehyde-based glue begins to polymerise within 20–30 seconds, has excellent strength and bonds to tissues within two to three minutes regardless of temperature or whether the adhesive is wet or dry. It can be employed in managing patients with complex cardiac repairs or for managing dissecting aortic aneurysms, in which it can help seal the separating layers of the aortic wall. Cited potential complications include vascular strictures at the site of application or embolisation of adhesive substance from the local site to a distant site, such as the arm or leg.(2,15)
Latest advances in surgical adhesives and sealants 
The majority of products discussed earlier are typically presented as powders with solutions in ‘kit form’. They are solubilised by the scrub nurse before use and delivered to the target tissue via a syringe, where they cure on the tissue surface to generate a bond and cross-link with their respective components to provide a ‘gel’ with cohesive strength. Within the last four years a dry product has been developed. It comprises a preformed film with intrinsic mechanical strength, which incorporates materials that react on contact with wet tissue forming a strong bond. This range of surgical sealant films, marketed by Tissuemed, are available for internal surgical use as adjuncts for preventing blood, fluid (such as cerebrospinal fluid) and air leaks in general, neurological,(18) thoracic, head and neck surgery. This synthetic, resorbable film incorporates two biocompatible polymers: poly(lactide-co-glycolide), which provides the product with cohesive strength; and a functionalised  polymer, ‘Tissuebond’, which offers both contact adhesion (via polyacrylic acid groups) and sustained adhesion through the formation of covalent bonds between the polymer and protein-rich tissue surfaces. 
Conclusions
There is a vast array of topical sealants available for the surgeon to use (Tables 1 and 2). The agent of choice depends not least upon on the nature of the bleeding or leak, the anatomical site and the type of tissue. Furthermore, the surgeon’s preference and experience along with availability and cost of the sealant add to the equation. What is evident is that the sealant should be used with due thought and care to the outcome and potential complications. The use of surgical sealants should not compromise proper surgical technique and attention to adequate haemostasis and wound closure.
References 
  1. Lauto A et al.  Adhesive biomaterials for tissue reconstruction. J Chem Technol Biotechnol 2008; 83:464–72. 
  2. Achneck HE et al.  A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg 2010; 251:217–28. 
  3. Rousou J et al.  Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study. J Thorac Cardiovasc Surg 1989; 97:194–203. 
  4. Spotnitz WD. Commercial fibrin sealants in surgical care. Am J Surg 2001; 182:8S–14S. 
  5. Schexneider KI. Fibrin sealants in surgical or traumatic hemorrhage. Curr Opin Hematol 2004; 11:323–26. 
  6. Kouba E et al. Partial nephrectomy with fibrin glue repair: measurement of vascular and pelvicaliceal hydrodynamic bond integrity in a live and abbatoir porcine model. J Urol 2004; 172:326–30. 
  7. Liu CD et al. Fibrin glue as a sealant for high-risk anastomosis in surgery for morbid obesity. Obes Surg 2003; 13:45–48. 
  8. Lillemoe KD et al. Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial. J Gastrointest Surg 2004; 8:766–72.  
  9. Carless PA, Henry DA. Systematic review and meta-analysis of the use of fibrin sealant to prevent seroma formation after breast cancer surgery. Br J Surg 2006; 93:810–19.
  10. Sierra DH et al. Modulation of mechanical properties in multiple-component tissue adhesives. J Biomed Mater Res 2000; 52:534–42. 
  11. Jackson RM, New and potential uses of fibrin sealants as an adjunct to surgical hemostasis. Am J Surg 2001; 182:36S–39S.
  12. Ono K et al. Photocrosslinkable chitosan as a biological adhesive. J Biomed Mater Res 2000; 49:289–95. 
  13. Ong CC et al. Comparing wound closure using tissue glue versus subcuticular suture for pediatric surgical incisions: a prospective, randomised trial. Pediatr Surg Int 2002; 18:553–55. 
  14. Van den Ende ED et al. Adhesive bonds or percutaneous absorbable suture for closure of surgical wounds in children. Results of a prospective randomized trial. J Pediatr Surg 2004; 39:1249–51. 
  15. Sileshi B et al. Management of surgical hemostasis: topical agents. Vasc 2008; 16:S22–28. 
  16. Chapman WC et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg 2007; 205:256–65. 
  17. Ellegala DB et al. Use of FloSeal hemostatic sealant in transsphenoidal pituitary surgery: technical note. Neurosurgery 2002; 51:513–15.  
  18. Della Puppa A et al. Use of a new absorbable sealing film for preventing postoperative cerebrospinal fluid leaks: remarks on a new approach. Br J Neurosurg 2010; 24:609–11.