FIBRIN GLUE

Didem Demirbaş

A) TISSUE ADHESIVES

Tissue adhesives can be defined as any substance with characteristics that allow for polymerization. This polymerization must either

i)                    hold tissues together,

ii)                   serve as a barrier to leakage.

 Desired properties of a tissue adhesive:

i)                    It must hold tissue in place to allow the healing of cut or separated areas.

ii)                   The optimal adhesive should break down.

iii)                 It should not hinder the progress of the natural healing process. Preferably, the agent should promote the natural mechanism of wound healing and then degrade.

iv)                 The agent must act locally.

v)                  It must be safe (when fibrin glue was first introduced, it was exluded from practical use due to risk of infectious transmission) (1).

Practical use of adhesives

Tissue adhesives are utilized in three categories:

i)                    Hemostatis (for example, by improving in vivo coagulation systems, tissue adhesion itself has a hemostatic aim and it is related to patient clotting mechanisms)

ii)                   Tissue sealing : primary aim is to prevent leaks of various substances, such as air or lymphatic fluids.

iii)                 Local delivery of exogenous substances such as medications, growht factors, and cell lines.

Types of tissue adhesives

-         Fibrin sealants,

-         Albumin-based compounds (glutaraldehyde glues)

-         Cyanoacrylates

-         Hydrogels (polyethylene glycol polymers)

-         Collagen-based adhesives

B) FIBRIN GLUE

The use of clotting substances from blood for hemostasis dates from 1909 (2). Tissue adhesive property of fibrin was described in 1940 (3). The combination of fibrinogen and thrombin was first used clinically in 1944 to improve the adhesion of skin grafts to burned soldiers. Its poor adhesive qualities and risk of transmission of infection were disappointing at that time (4). It became commercially available in Europe in the early 1980s. The year 1972 was marked by a renaissance of fibrin sealing developed in Vienna for reuniting nerves in humans (2).

The development of fibrin sealant has been gradually advanced and optimized as the concentrated plasma fibrinogen and bovine thrombin. This description of the composition has led to the widespread use and acceptance of fibrin sealant in surgical procedures.

Action mechanism of fibrin glue

The real value of fibrin glues lie in their unique physiologic action, which mimics the early stages of the blood coagulation process and wound healing, the part of the normal coagulation cascade to produce an insoluble fibrin matrix. Fibrinogen is a glycoprotein made of three pairs of disulfide-linked polypeptides. In the natural mechanism, fibrinogen polypeptides are cleaved to soluble monomers by the action of activated thrombin. These monomers are cross-linked into an insoluble fibrin matrix by the aid of activated factor XIII (Figure 1).

Figure 1 : Fibrin clot formation (5).

The adhesive qualities of consolidated fibrin sealant to the tissue may be explained in terms of covalent bonds between fibrin and collagen, or fibrin, fibronectin and collagen.

Fibrin glue acts as both hemostatic and as a sealant. They are bioabsorbable (due to in vivo thrombolysis). Degeneration and reabsorption of the resulting fibrin clot is achieved during normal wound healing. Fibrin sealants are not associated with inflammation and tissue necrosis, unlike the cyanoacrylates.

 

Composition of Fibrin Sealants

The most basic fibrin sealants consist of combinations of trombin and fibrinogen. Some sealants also include small doses of calcium chloride and factor XIII or antifibrinolytiscs like aprotinin. Antifibrinolytic agents are used to prevent the naturally occurring clot degradation. Commercially available fibrin sealants contain higher fibrinogen concentration.

How to make fibrin glue ?

Fibrin glue is initially homemade in the operating room by surgeons. Nowadays, fibrin glue is commercially available with following names:

i)                    Tisseel VH

ii)                   Beriplast P

iii)                 Bolheal

iv)                 Hemaseel APR

v)                  Quixil

In home made fibrin glue formation, single donor cryoprecipate was used rather than pool donated one. The source of clotting factors is either pooled plasma or bovine source in commercially available ones.

How to apply fibrin sealant?

Tisseel VH fibrin sealant is one of the commercially available fibrin sealants. The kit contains

-         Freeze dried form of sealer protein concentrate (human fibrinogen)

-         Aprotinin (bovine)

-         Thrombin (human)

-         Calcium chloride

First two components are mixed in one syringe while other two were mixed in another syringe. By using the specially designed applicator, two components were delivered with equal volume (Figure-2).

Figure-2 : Commercially available Tisseel VH fibrin glue kit (6).

Strength of the seal : Tisseel VH fibrin sealant attains approximately 70% of its strength in the first 10 minutes. Full strength is reached in 2 hours.

Price : 4 mL of Tisseel VH is approximately $264 (7).

Another application method for fibrin glue was described by Baker and Spontnitz. This technique uses spray bottles, rather than syringes, to deliver fibrin glue to a larger surface area. The spray method is particularly useful in reoperative fields with more diffuse sites of bleeding (4).

C) APPLICATIONS OF FIBRIN GLUE

Tissue sealing with fibrin sealant not only results in the reduction of perioperative hemorrhage, but also in the reduction of other fluid (for example, bile) or air leakage and the prevention of fistula formation.

Usage of fibrin sealants

i)                    an adjunct to hemostatis

ii)                   wound healing

iii)                 tissue adhesion

iv)                 drug delivery

Applications

1.      Cardiothoracic surgery

The effectiveness of fibrin sealant on hemostatis in cardiothoracic surgery is important to the clinical outcome; successful local hemostatis reduces blood loss, operative time, and the need for resternotomy in these high risk patients (3).

2.      Cardiovascular surgery

Bleeding after open-heart surgery is a great problem in cardiac surgery. Due to hemostatic abnormalities, reoperation to control prolonged bleeding may be necessary. Fibrin sealant was significantly superior at producing hemostatis compared with conventional topical agents, such as collagen-coated dressings (Figure 3).

Figure 3 : Comparison of fibrin sealant and topical agent in maintenance of hemostatis after cardiovascular surgery (3).

Advantages of fibrin glue in cardiovascular surgery

-         Improvements in local hemostatis,

-         Vascular graft preparation,

-         Reduced blood loss,

-         Reduced operative time, reduced reoperation and operative mortality.

3.      Thoracic surgery

Fibrin glue is used for sealing air leaks from lung procedures (even as treatment for bronchopleural fistulas). Thoracic surgery frequently involves pulmonary resection and decortications. The consequences of such surgical intervention include hemorrhage and air leaks. Retrospective analyses indicate that bronchopleural fistulae occur in 2 % to 3 % of patients after pulmonary resection, followed by a mortality of 15 % to 20 % (Figure 4). These complications can be overcome by the use of fibrin sealants.

Figure 4 : Effect of fibrin sealant in thoracic surgery (3).

In another study, tissue sealing of lung significantly reduced the incidence of post-operative air leakage from 66% in the control group to 39% in the fibrin sealant group (3).

4.      Hepatic and pancreatic surgery

Raw cut surfaces of soft tissues such as liver and lung cannot be isolated and secured by conventional techniques such as suturing. Trauma surgeons use fibrin glue for spleen and liver lacerations. The management of these surfaces is important for preventing intrapertoneal complications, such infection, abscess formation, and sepsis which may lead hemorrhage, bile leakage, and fluid accumulation. Moreover, bile fluid is a severe irritant to peritoneum and the prevention of bile leakage using a fibrin sealant is highly desirable. Over the past 10 years, fibrin sealant has been used successfully as a tissue sealant in hepatobiliary surgery (3).

5.      Neurosurgery

Fibrin glue is used for dural closure by neurosurgeons to prevent cerebrospinal fluid leakages. The management of cerebrospinal fluid (CSF) fistulae is important. Fibrin sealant has been used in neurosurgical procedures for the prevention of CSF leakage from fistulae. From a total of 62 patients, 44 patients were operated using fibrin sealant to close the CSF fistulae. All patients wre successfully treated with no recurrence of fluid leakage or other complications (100%). For 18 patients, CSF fistulae were closed by cyanoacrylate and 38.9% had recurrent leakage and 16.7% had postoperative meningitis as a complication (3).

6. Aesthetic surgery

Aesthetic surgeons in Europe have routinely used fibrin-based glues in place of sutures, which has enabled them to avoid the use of drains for patients undergoing facial cosmetic surgery. There are basically two advantages of avoiding the use of drains and dressings: the postsurgical time is reduced by not putting on and removing the usual bulky dressings, and swelling, hematoma formation is reduced. Tissue adhesives have been reported to decrease the incidences of postoperative hematomas and edema, enable painful suture removal to be avoided, and, in some cases, facilitate early recovery and greater patient satisfaction.

Plastic surgeons especially use adhesives to control burn bleeding after debridement and  as adjuncts in surgery necessitating flaps. Skin grafting is the simplest and most effective method used to resurface large burn wounds. The graft initially adheres to its new bed by a thin layer of fibrin and nourishment of the graft occurs by plasmatic imbibition. Further ingrowth of blood vessels and fibrous tissue from the wound results in permanent adherence of the graft to its recipient site known as graft “take.” This process can be hindered by collection of blood between the graft and bed, by shearing and by infection. The face is highly vascular and diffuse bleeding is difficult to control following burn wound excision.  Traditionally, to overcome the problem of hematoma, the grafts are meshed to enable any fluid collection to drain. Unfortunately meshing produces scarring which impairs the final cosmetic result. Careful suturing can minimize shearing, but takes time, may promote bleeding and also leaves scars. The fibrin glue therefore has several advantages in the excision and skin grafting of facial burns:

-         It provides good hemostasis and helps prevent hematoma formation,

-         It minimizes the use of sutures, which save operating time,

-         It avoids further bleeding during passing of the sutures.

A technical disadvantage may be that shaping of the grafts has to be carried out prior to gluing, as there is a little time for manipulation (5).

7. Endoscopic surgery

Plastic surgeons are utilizing fibrin glue for the management of wrinkles of the forehead and of the aging face. The technique avoids the classic coronal incision, utilized for the browlifting, thus minimizing morbidity. The adhesive not only helps to secure the forehead and scalp flaps in place, but also works as a hemostatic agent, decreasing hematoma formation and bruising (Figure 5) (8).

a) Patient before the operation

    

b) Left eye is sutured, right one is fibrin glued. c) No difference in long term.

d) After the operation.

Figure 5 : Comparison of suture and fibrin glue in a eye operation (8).

8. Prevention of seroma formation

The collection of serous fluids after operations is a very treathening problem and should be prevented. It can cause significant morbidity and delayed recovery. It can appear after a mastectomy and axillarymade dissection, soft tissue dissection (abdominoplasty, breast reduction, facelift), and muscle harvesting. The complications include pain, wound infection, flap necrosis, and increased costs. Lindsey et al. described a rat mastectomy model for seroma prevention using fibrin glue (8). They demonstrated that the sealant reduced seroma formation in the rat model. Kulber and co-workers have demonstrated the advantage of fibrin sealant and the reduction of seroma formation after soft tissue dissection and muscle harvesting in the rat model. The rat latissimus dorsi muscle, shown to be a reliable model for creating seromas, and the sealant effectively prevented seroma formation when applied intraoperatively. Wound healing in this model was also improved with intraoperative fibrin sealant application (8).

9. Fibrin sealants in bone healing

An ideal adhesive for use in bone repair should promote osteoblastic activity rather than retarding it. Cyanoacrylates cause adverse bone reaction. Their space occupying nature prevents or retards healing and their degradation products are harmful.

Pfluger claims that fibrin sealants (FS) appear to accelerate the incorporation of bone implants (2). However, Albrekstsson and his co-workers could not prove any positive effects of FS in a bone growth chamber (2). In bone transplantation, it is reported to improve a homogeneous incorporating of the implant due to an accelerated vascularization. There is no indication for FS in ordinary transplantation of cancellous bone. If used, it should be applied in a thin layer. There is evidence that FS accelearates neovascularization and influences the early phase of bone repair. FS allows sufficient stabilization of small bone or osteochondral fragments.

In a recent study, osteoinductive action of fibrin glue (FG) was reported by  Abiraman et al. (9). They evaluated the osteoinductive property of FG when coated with calcium phosphate and glass ceramics and implanted in the extraskeletal site of male Swiss albino mice. As the implant materials, they used hydroxyapatite (HA) porous granules (300–350 mm), bioactive glass system (BGS)-AW type and calcium phosphate calcium silicate system (HABGS) non-porous granules (300–350 mm). They used uncoated granules (as the control group) and granules coated with 2.5 mg FG and 5mg FG (as the study group). They were implanted in the quadriceps muscle of mice and they were sacrificed after 28 days. Histologically, HA, BGS and HABGS implanted animal groups showed good healing response. However, neo-osteogenesis was observed only in the BGS and HABGS granules impregnated with FG. Furthermore, they observed more conspicuous bone formation in 5mg FG coated BGS and HABGS granules when compared with 2.5 mg FG coated BGS and HABGS granules. On the contrary, the uncoated granules did not show any de novo bone formation. This experimental study provides an evidence of the positive role of FG as a potential osteoinductive biologic tissue adhesive (9).

 

10. Drug delivery

MacPhee and co-workers have demonstrated fibrin to be a good delivery vehicle for local administration of drugs (8). It has the ideal characteristics to place such a role. It is found as the site of virtually all tissue injury and is broken down and replaced by healing tissue as part of the body’s natural healing process. It controls bleeding and remains firmly fixed in place until it is naturally biodegraded. Fibrin sealants are capable of delivery chemotactic, growth promoting, and differentiation factors to induce both soft and hard tissue production or the innovation of undesirable proliferation. It has been used to delivery conventional pharmaceuticals in the form of antibiotics and chemotherapy drugs for prolonged periods.

A very recent paper on bladder replacement by using a rat model by Schoeller et al. (10) also studied the use of fibrin glue for cell delivery.  Their aim was to compare a standard culture media and fibrin glue as a delivery vehicle for ex vivo expanded primary urothelial cell cultures for autologous implantation onto a prefabricated capsule-pouch. When using fibrin glue as the delivery conduit, they were able to produce an adherent and viable urothelial cell layer, whereas standard culture media consistently failed to produce such results. Furthermore, they demonstrated that a gracilis muscle flap can be seeded with autologous cultured urothelial cells suspended in fibrin glue (10).

 

Fibrin glue is expected to play a significant role in future clinical applications of local delivery of drugs and biologics due to the diversity of compounds that can be delivered by fibrin sealants, the compatibility of fibrin sealants with living tissue and their well-established clinical safety.

 

11. Liver biopsy

Liver biopsy is frequently necessary for candidate evaluation or histologic follow-up of transplanted livers. Although generally considered to be safe, it carries a risk of complications in up to 0.5% of cases; hemorrhage being the most important. Another option is the so-called plugged percutaneous liver biopsy (PPLB), which uses direct injection of a plugging material into the biopsy tract. Different materials have been used: Tissucol, absorbable gelatin sponge, or hemostasis coils. Arbizu et al. (11), have plugged fibrin glue  in 30 percutaneous liver biopsies on 16 patients after liver transplantation, only two complications were observed. Pre-PPLB and post-PPLB hemoglobin concentrations were not significantly different. Although the technique should be improved, it provides an easier alternative for liver biopsy.

12.  Use of fibrin glue in dentistry (Selected paper)

Effects of fibrin glue on wound healing in oral cavity

(By Yücel et al.) (12)

Aim: In this study healing properties of a wound, located in the oral cavity and treated with FG was compared with conventional sutures, assessed in a study with control group.

Material-Methods:

42 Sprague Dawley rats were used as experimental animals, they were 6-8 week old and weighed 250+20 g.The study group contains 24 rats and their first molar tooth was extracted with some cortical bone by a curved artery clamp and bone margins were curetted with a small bone curette. Approximation of the wound surfaces were accomplished using Tisseel FG. For the control group, 18 animals were used. They were treated in the same way but 5/0 silk suture was used instead of FG for wound closure. The sutures were removed at seventh postoperative day. In both the control and the study group, the rats are categorized to 3 groups, which are sacrificed 2, 4, and 6 weeks after the operation. Their jaws were removed, fixed and after sectioning histological analyses were carried out. They examined for inflammatory reaction, new bone formation, regeneration of epithelium, fibrosis, foreign body reaction, abscess formation, and necrosis.

Results:

For the study group, normal healing at wound site was observed. No infection or delayed healing was observed at 2, 4, and 6 weeks. It can be said that fast form of FG favoured the healing of the wound in the oral cavity. On the contrary, the use of silk sutures resulted with foreign body reaction, fistula formation in one rat (4 weeks) and submental abcess in another rat in control group (6 weeks).

Conclusion :

It is known that polytetrafluoroethylene (ePTFE) membranes may guide tissue regeneration on calvarial defects of rats, via forming a closed space filled by a blood clot which provides a favourable environment for osteogenic cells. Since it is impossible to use PTFE in oral cavity defects, FG is a good alternative for bone healing process in oral cavity. Indications for the FG are mainly limited by two factors; the cost and the risk of hepatitis.

Comment :

The paper is good in terms of comparing suturing and fibrin glue. The reason I wanted to concentrate on this paper is that it is a good illustration of the effectiveness of fibrin glue even in a region where fibrinolytic activity is very great due to saliva. The researchers made some histological assays and the degree of inflammation etc which can be thought as a subjective evalulation was carried out by the same person to prevent confusions. However, the illustrations were not clear enough (that’s why I could not include any). In my opinion, its usage in dentistry will reduce the suffering and reduce operation time at dentist’s desk. This study should be supported with clinical trials of less difficult operations. As fibrin glue is used in different surgical procedures, better understanding of its limits will be attained.

13. Other Practical Applications of Fibrin Glue

Fibrin glue can be used as wound dressings. Absorbabale fibrin adhesive bandages (AFAB) can be directly used in the control of battlefield wounds, immediate local control of bleeding can be achieved. Local hemostatis means initial stabilization of the patient. Its another application may be as a  hemostatic dressing in the operating room which is used instead of a sponge.

D) ADVERSE EFFECTS OF FIBRIN GLUE

Fibrin glue was monitored for adverse effects including inflammatory reactions, allergic reactions, and viral infections. Prolonged inflammation have not been reported for fibrin sealants. There have been no reports of human immunodeficiency virus seroconversion after the use of fibrin sealant or hepatitis B or hepatitis C (by 2001). Analysis of 5 year data on adverse events associated with the use of fibrin sealant showed that the incidence of adverse events was 1 in every 98,933 applications. Overall, fibrin sealants are extremely well tolerated by patients (3).

The source of clotting factors is either pooled plasma or bovine source. Pooled plasma has a risk of viral transmission. Only reported transmission from fibrin sealants is parvovirus B19 (they are carefully screened before used). Hino et al recently reported three cases of iatrogenic parvovirus B19 infection after the use of fibrin sealant. This viral transmission was attributed to the use of dry-heat viral inactivation, which is not effective against nonenvelope viruses (3).

Bovine proteins can cause development of autoimmune reactions to native thrombin and clotting factors. The use of isolated blood products is a great risk. At this point, the most promising source is the development of recombinant thrombin and fibrinogen. However, recombinant blood products are not currently is in use (by 2001).

The differences in outcome after the use of fibrin sealant may be the result of surgical technique, fibrin sealant composition, or the kind of disease that required surgery.

It can be concluded that if tissue adhesives are used correctly, they improve the healing process while their improper usage makes the problem worse. If the adhesive polymerizes before the tissue is approximated, then the adhesive serves as a barrier to wound healing.

CONCLUSION

The action of fibrin glue for soft tissue adhesion is very important. Besides its adhesive effects, its sealant effect which prevents air or fluids to leak is a very useful for better control during surgery. Fibrin sealant can reduce operative time and prevent complications associated with surgical intervention (hemorrhage, fluid and/or air leaks, fistula formation) which may result in reduces postoperative discomfort and hospital stay for patients. Although the strength is lower with respect to other adhesives and sutures, the wide range of applicability of fibrin glue, its non-toxic, biodegradable, biocompatible nature make it even more promising in near future. For better comparisons of its effect with other adhesives, especially the commercially available fibrin glues should be used for consistent results. The contradictions in the experimental findings of different researchers is mainly the differences in the source of fibrin glue used and in its handling. In order to understand its value better, different experiments should be conducted and fibrin glue should be used for different applications. The recent studies which focus on delivery of drugs or cell lines with the aid of fibrin glue are providing promising results and fibrin glue can be a key element in tissue engineering studies in future. The development of recombinant thrombin and fibrinogen will eliminate the risks associtated with fibrin glue and fibrin glue will be used more commonly even with more diverse applications.

REFERENCES

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4. MacGillivray, E.T., (2003) “Fibrin Sealants and Glues”, J Card Surg; 18; 480-485.
5. Gulati S, Milner SM. Use of fibrin glue in excision and grafting of facial burns. J Burns & Surg Wound Care [serial online] 2002;1(1):18. Available from: URL: http://www.journalofburns.com
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8. Saltz, R.; Zamora, S.; (1998) “Tissue Adhesives and Applications in Plastic and Reconstructive Surgery”, Aesth. Plast. Surg., 22:439–443
9. Abiraman, S.; Varma, H.K.; Umashankar, P.R.; John, A. (2002) “Fibrin glue as an osteoinductive protein in a mouse model”, Biomaterials, 23, 3032-3031.
10. Schoellera, T.; Neumeisterb M.W.; Huemera, G.M.; Russell R.C.; Lilleb, S.; Otto-Schoellera, A.; Wechselbergera, G., (2004) “Capsule induction technique in a rat model for bladder replacement: an overview”,  Biomaterials, 25, 1663–1673.
11. Arbizu, E.A.; San Roma´ n, A.L; Gonza´ lez, G.M.; Foruny Olcina, F.R.; Garcia-Hoz Rosales, F.; Ba´ rcena Maruga´ n, R.; Plaza Palacios, G.; Gil Grande, L.A., (2003) “Fibrin-Glue Sealed Liver Biopsy in Patients With a Liver Transplantation or in Liver Transplantation Waiting List: Preliminary Results” Transplantation Proceedings, (Technical Aspects), 35, 1911–1912.
12. Yücel, E.A.; Oral, O.; Olgaç, V.; Oral, C.K.; (2003) “Effects of fibrin glue on wound healing in oral cavity”, Journal of Dentistry, 31, 569–575.
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14. http://www.haemacure.com/en/products/hseelAPRClinical.html