[Sections of this paper originally appeared in the journal Thrombosis
and Haemostasis 1995;74:482-485. These excerpts are reprinted with permission.
References for this excerpt have been deleted and are available upon request.]

INTRODUCTION
Although the quality of surgical practice in the United States today is world renowned, the American surgeon suffers from a lack of a commercially available, government approved adhesive available in the day-to-day armamentarium of tools. An ideal tissue adhesive would be widely applicable. An effective adhesive would significantly augment surgical hemostasis and tissue adherence. An ultimate agent should have at least the following attributes (Table 1). The material must be safe so that no significant dangers are associated with its application or the presence of its degradation products. The tissue adhesive must also be effective. The superior characteristics of effectiveness which are necessary include: internal bonding strength, surface adherence strength, capacity for enhancing clot formation, and wound healing and tissue regeneration ability. The agent also needs to be readily usable. It should be ready for easy application within a period of minutes. The tissue adhesive should be workable so that it is easily shaped and placed in the appropriate location, yet relatively quickly solidifying. The product needs to be reasonably priced so that it is affordable and can be widely used in a cost conscious environment. Most importantly, in the United States today, the adhesive must be approvable by the Food and Drug Administration.

New applications at Virginia. A number of new uses for fibrin sealant have been developed, while fibrin sealant has been in use at this hospital (Table 2). These improvements have been made possible because surgeons had the opportunity to employ this agent on a wide variety of services using an efficient blood bank monitored system. As clinicians develop skill in using this product, increased confidence has allowed new applications to be explored and successfully utilized.

DISCUSSION
Benefits. Fibrin sealant has been an extremely effective and widely used adjunct to surgical operations. It has been applied successfully in more than 90% of cases and has been utilized in approximately 5% of the operations performed yearly at this institution. The spray technique has been extremely helpful in allowing for extensive and uniform mixing of thrombin and fibrinogen. This technique has been particularly helpful for control of diffuse slow bleeding over large surfaces. The use of sponges of cellulose soaked in fibrinogen and then activated with thrombin has been the most effective method for controlling significant localized bleeding. The transfusion requirements of patients undergoing major surgical procedures such as cardiac surgery or burn eschar debridement may be reduced by the use of fibrin sealant. However, bleeding which cannot be controlled by pressure to allow the fibrin sealant to completely form will not be successfully managed using these techniques. Fibrin sealant is not a substitute for meticulous surgical technique and cannot reduce bleeding when traditional surgical methods such as a suture are required.

Significant benefits to fibrin sealant use have been noted not only for control of bleeding but also for control of leakage of air and other body fluids. In addition, tissue apposition requirements can be achieved using fibrin sealant as is demonstrated in its ability to enhance skin graft survival. Researchers at this institution have previously published a method of deriving concentrated single donor human fibrinogen using cryoprecipitation. This method has been used successfully over a period of ten years in more than 3,000 patients. It provides for significant quality control using established blood bank procedures and avoids a waste of unstable clotting factors. In addition, an autologous system for producing fibrinogen from donors about to undergo surgical procedures has been instituted using the same method and has been particularly useful in stable patients undergoing surgery such as mastectomy. A clear advantage of autologous donation is elimination of blood borne disease transmission.

Risks. The dangers associated with the use of fibrin sealant can be linked to the individual component producing the sealant, as well as the fibrin clot. Specifically, fibrinogen from non-autologous sources can be associated with transmission of blood borne infections, including HIV and hepatitis. Topical bovine thrombin has recently been reported to be associated with hypotension and the formation of abnormal antibodies to factor V, which may produce significant coagulopathy. There can also be risks associated with the formation of uncontrolled clot in undesirable locations. This includes danger of clotting in cardiopulmonary bypass circuits employed during cardiac operations and the at least theoretical danger of clotting draining chest tubes thereby blocking effective drainage. Fibrin sealant or thrombin itself may be inadvertently injected into the arterial system and can cause dangerous embolization or intravascular coagulation.

Additional developments. Several recent reviews have documented a wide variety of additional uses for fibrin sealant, including its use for achieving hemostasis in patients with coagulation disorders; improving results following face lifts; repairing dural defects in craniofacial resections; assuring hemostasis following tooth extraction in anticoagulated patients; closing incisions following blepharoplasty; performing safe pancreaticojejunostomy; closing rectovaginal and other complex fistulas; treating pneumothoraces in premature infants; closing multiple ventricular septal defects; and reinforcing choledochotomy closures.

In addition, fibrin sealant has been used as a carrier for other compounds. Thus, it has been used to slowly release antibiotics at the site of an infection, to deliver chemotherapeutic agents to tumor cells, to deliver growth factor for healing of cartilage, and endothelialization of vascular grafts. Reports of bone induction using this agent as a carrier for demineralized bone have recently appeared.

Innovative methods for producing fibrin tissue adhesives are being refined. Three technologies in particular are currently competing in order to develop a fibrin sealant product that may be even safer and more approvable by regulatory agencies in the United States (Table 3). Viral inactivation, autologous donation, and recombinant production are presently in use by manufacturers in an attempt to develop a marketable product.

Implications. There is increasing clinical and manufacturer pressure to license a safe and efficacious commercial product for use in the United States. Such a fibrin sealant might have significant advantages. It could reduce the wide-spread use of single donor fibrin sealant and topical bovine thrombin. Thus, an improved safety fibrinogen source as well as a human source of thrombin might further reduce the risk of blood-borne disease transmission associated with fibrinogen and abnormal antibody formation associated with bovine thrombin. A number of safety and efficacy studies are presently in progress and the marketplace is highly competitive with significant industrial investment. The market for fibrin sealant is large with a wide variety of significant applications existing in the modern surgical environment for a safe and efficacious product. The present competition should result in improved patient care and a significant addition to the surgical armamentarium of the modern clinical surgeon.

CONCLUSION
A single donor system for producing fibrin sealant has been in place at the University of Virginia for the past 17 years. It has been used successfully in over 3,000 patients on a wide variety of surgical services. A number of new and innovative uses have been documented. A significant increase in manufacturer interest and investment is occurring and it appears as though the regulatory environment is changing in the United States such that approval of a commercial product is on the horizon.