How does fibrin glue work

A repeat sealing could be conducted if the fistula persists for 5 days after the first procedure. After the day period, patients who fail to achieve medical closure are evaluated to further exclude possible factors disturbing healing, such as infection, foreign body, etcetera.

Fistula drainage will be evaluated every day until the drainage decreases to zero, which is defined as fistula closure [ 17 ]. It also needs confirmation by contrast enhanced computed tomography at each follow-up visit to verify the complete closure of internal and external openings of the fistula tract.

Other SOC measures can be conducted when needed. The primary outcome of the trial is fistula closure time defined as the interval between the day of enrollment and day of fistula closure during the day treatment period.

Fistula closure is defined as complete closure of the fistula tract and internal and external openings later, which will be confirmed by contrast enhanced computed tomography at each follow-up visit where there is no drainage or any sign of inflammation [ 17 ]. In addition to the primary outcome measure of fistula closure, secondary outcomes include closure rates up to 14 days, closure rates up to days, fistula recurrence rates and the incidence of adverse events and severe adverse events up to days defined as an event that was fatal or life-threatening, led to additional hospitalization or disability or required an intervention to prevent one of these outcomes.

In case of daily output less than ml, the inclusion criteria will be assessed, and imaging examination will be performed to exclude abscesses, obstruction, etcetera. Then participants are randomly allocated to Group A autologous fibrin glue , Group B commercial fibrin glue or Group C drainage cessation. The study period is set as 14 days after the day of enrollment, and fistula drainage will be evaluated every day. All patients are followed up for at least days.

The outpatient visits will be scheduled for 1 month, 3 months and 6 months after enrollment Fig. Study design. Patients are randomly allocated to group A autologous fibrin glue , group B commercial fibrin glue or group C drainage cessation.

After glue application or drainage cessation, fistula drainage will be evaluated for 14 days, during which a maximum of three times of glue sealing will be conducted for patients in groups A and B.

Both efficacy and safety outcomes will be assessed during the whole study period. The sample size is to be calculated based on detecting the minimal, clinically relevant difference in the success rates of the three arms. In this way, 51 patients per group are needed for this trial based on an alpha of 0. A clinical coordinating center in each participating site is established to identify subject eligibility for the study and to provide support to investigators and study personnel throughout the study period.

The coordinating center consists of a principle investigator and a well-trained study coordinator. Research coordinators are required to screen all fistula patients in each study center for eligibility once a day, either the morning or afternoon.

The patient cannot be enrolled until their eligibility is confirmed by the treating physician. Then, the study coordinator will obtain written informed consent from the patient. Patients will be consecutively enrolled at each of the participating centers whenever a study coordinator is available for enrollment.

Consent will be obtained from participating clinicians before or at the time of patient consent. Stratification for age will be performed, and an equal distribution between treatment arms ratio of will be warranted. The principle investigator in each coordinating center informs clinicians of the allocation sequence via a central telephone to ensure concealment. Eligible patients who have given consent will be randomized into any of the three groups. A case report form is used to collect the data for each patient.

Assessments are made at the screening period, inclusion D0 and on days 1 to Assessments include fistula assessment location, output, duration, and length of fistula tract , monitoring drainage, catheter, tubes, and adverse events , laboratory tests hematology, biochemistry, urinalysis, and pregnancy test at inclusion only , and microbiology blood cultures and cultures of isolates from fistula tracts.

Data on adverse events, compliance and concomitant treatments are collected at each visit. Participants will be evaluated every day until the 14th day after randomization.

All documents collected in this study will be stored safely in confidential conditions. Study documentation will be archived for a period of 5 years after the study. Cox proportional hazards models and the Kaplan-Meier method will also be applied.

The DMC is independent of the study organizers. During the period of recruitment to the study, interim analyses will be supplied together with any other analyses that the committee may request. This may include analyses of data from other comparable trials. The frequency of interim analyses will depend on the judgement of the Chair of the DMC MY , in consultation with the study organizers.

However, we anticipate that there might be two interim analyses and one final analysis. The trial will not be stopped in case of futility. All adverse events will be recorded and closely monitored until resolution or stabilization or until it has been shown that the study intervention is not the cause of the event. The chief investigator will be informed immediately of any serious adverse events and will determine in cooperation with the treating physicians the seriousness and causality of these events.

All treatment-related serious adverse events will be recorded and reported to the Ethics Committee as part of the report. Unexpected serious adverse events will be reported to the Ethics Committee within the relevant time frames. The chief investigator will be responsible for all adverse event reporting. All site staff will be appropriately trained in the procedures to follow and the forms to use during the study protocol prior to study initiation.

Regular central monitoring for all studies and site monitoring, as determined by the trial-specific risk assessment, will be used to ensure that all adverse events are identified and acted on appropriately. The research team ensures that this study is being conducted in accordance with the principles of the Declaration of Helsinki [ 18 ]. The trial will also be conducted in accordance with both international and Chinese ethical guidelines for biomedical research involving human subjects [ 19 , 20 ].

The study protocol, informed consent form, participant information sheet, and any further patient documents have been submitted to the Institutional Review Board of the Ethics Committee of each study site for written approval. Details of all approving institutional review boards can be found in Additional file 1.

Approval has been obtained from the Ethics Committee for all substantial amendments to the documents originally approved. The modifications will require a formal amendment to the protocol. Such amendments will be agreed on by the sponsor and approved by the Ethics Committee prior to implementation, and the health authorities will be notified in accordance with local regulations.

Administrative changes to the protocol are minor corrections that have no effect on the way the study is to be conducted. Journal of the American College of Surgeons. Use of fibrin sealant to reduce bloody drainage and hemoglobin loss after total knee arthroplasty: a brief note on a randomized prospective trial. Journal of Bone and Joint Surgery A. Fibrin sealant facilitates hemostasis in arteriovenous polytetrafluoroethylene grafts for renal dialysis access.

Fibrin sealant improves hemostasis in peripheral vascular surgery: a randomized prospective trial. Annals of Surgery. Experience improves successful use of fibrin sealant in total knee arthroplasty: implications for surgical education. Fibrin sealant reduces perioperative blood loss in total hip replacement. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: components of the surgical toolbox. Hemostats, sealants, and adhesives II: update as well as how and when to use the components of the surgical toolbox.

Hemostats, sealants, and adhesives III: a new update as well as cost and regulatory considerations for components of the surgical toolbox. Hemostats, sealants, and adhesives: a practical guide for the surgeon. Package Insert, Tisseel, Baxter , Package Insert, Evicel, Johnson and Johnson, Transmission of symptomatic parvovirus B19 infection by fibrin sealant used during surgery. British Journal of Haematology.

Frequency of transmission of human parvovirus B19 infection by fibrin sealant used during thoracic surgery. Joch C. The safety of fibrin sealants. Cardiovascular Surgery. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations.

A multicenter study. Prospective, randomized evaluation of the efficacy of fibrin sealant as a topical hemostatic agent at the cannulation site in neonates undergoing extracorporeal membrane oxygenation. The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty. A prospective, randomized, multicenter study. A multicenter clinical trial to evaluate the topical hemostatic efficacy of fibrin sealant in burn patients. Journal of Burn Care and Rehabilitation.

Taylor LM, Jr. Prospective randomized multicenter trial of fibrin sealant versus thrombin-soaked gelatin sponge for suture- or needle-hole bleeding from polytetrafluoroethylene femoral artery grafts. Journal of Vascular Surgery. Comparison of a new fibrin sealant with standard topical hemostatic agents.

Journal of Cardiovascular Surgery. Randomized clinical trial of tranexamic acid-free fibrin sealant during vascular surgical procedures. British Journal of Surgery. Use of fibrin sealant as a hemostatic agent in expanded polytetrafluoroethylene graft placement surgery. Annals of Vascular Surgery. A randomized trial of aprotinin-free fibrin sealant versus absorbable hemostat. A prospective randomized study comparing fibrin sealant to manual compression for the treatment of anastomotic suture-hole bleeding in expanded polytetrafluoroethylene grafts.

Laparoscopic spray application of fibrin sealant effects on hemodynamics and spray efficiency at various application pressures and distances. Surgical Endoscopy and Other Interventional Techniques.

Nitrogenous subcutaneous emphysema caused by spray application of fibrin glue during retroperitoneal laparoscopic surgery. Journal of Anesthesia. Fibrin sealant in the United States: clinical use at the University of Virginia. Thrombosis and Haemostasis. Package Insert, Vitagel, Orthovita , Product Brochure rev.

Havener M, Marino A. Vitagel Swelling Study. Stryker Orthobiologics , Ref. A novel collagen-based composite offers effective hemostasis for multiple surgical indications: results of a randomized controlled trial. Effective control of hepatic bleeding with a novel collagen-based composite combined with autologous plasma: results of a randomized controlled trial.

Control of bone bleeding at the sternum and iliac crest donor sites using a collagen-based composite combined with autologous plasma: results of a randomized controlled trial.

TachoSil surgical patch versus conventional haemostatic fleece material for control of bleeding in cardiovascular surgery: a randomised controlled trial.

European Journal of Cardio-thoracic Surgery. Effectiveness of a new carrier-bound fibrin sealant versus argon beamer as haemostatic agent during liver resection: a randomised prospective trial. Hemostatic efficacy of TachoSil in liver resection compared with argon beam coagulator treatment: an open, randomized, prospective, multicenter, parallel-group trial. Efficacy and safety of TachoSil as haemostatic treatment versus standard suturing in kidney tumour resection: a randomised prospective study.

European Urology. Annals of Surgical Innovation and Research. Efficacy and safety of a fibrin sealant for adherence of autologous skin grafts to burn wounds: results of a phase 3 clinical study. Journal of Burn Care and Research. Hester TR, Jr. Aesthetic Surgery Journal. Fibrin glue from stored human plasma. An inexpensive and efficient method for local blood bank preparation. Platelet-rich fibrin matrix improves wound angiogenesis via inducing endothelial cell proliferation.

Wound Repair and Regeneration. Prakash S, Thakur A. Platelet concentrates: past, present and future. Journal of Oral and Maxillofacial Surgery. Spotnitz WD, Prabhu R. Fibrin sealant tissue adhesive—review and update. Applications of fibrin sealant in surgery. Surgical Innovation. Valbonesi M.

Fibrin glues of human origin. Best Practice and Research: Clinical Haematology. Recent clinical and investigational applications of fibrin sealant in selected surgical specialties. Organic glues or fibrin glues from pooled plasma: efficacy, safety and potential as scaffold delivery systems. Journal of Pharmacy and Pharmaceutical Sciences.

Fibrin chain cross-linking, fibrinolysis, and in vivo sealing efficacy of differently structured fibrin sealants. Journal of Biomedical Materials Research B.

Differences in biomechanical stability using various fibrin glue compositions for mesh fixation in endoscopic inguinal hernia repair. Cohesive behavior of soft biological adhesives: experiments and modeling. Acta Biomaterialia. Comparative study of lung sealants in a porcine ex vivo model.

Tensile strength of biological fibrin sealants: a comparative study. Suzuki S, Ikada Y. Sealing effects of cross-linked gelatin. Journal of Biomaterials Applications. New technique for application of fibrin sealant: rubbing method devised to prevent cerebrospinal fluid leakage from dura mater sites repaired with expanded polytetrafluoroethylene surgical membranes. New application method of fibrin glue for more effective hemostasis in cardiovascular surgery: rub-and-spray method.

Japanese Journal of Thoracic and Cardiovascular Surgery. Experimental study on effective application of fibrin glue. General Thoracic and Cardiovascular Surgery. Computational investigation of fibrin mechanical and damage properties at the interface between native cartilage and implant. Journal of Biomechanical Engineering. Engineering fibrin polymers through engagement of alternative polymerization mechanisms.

Allogeneic single-donor cryoseal produced from fresh-frozen quarantine apheresis plasma as alternative for multidonor or autologous fibrin sealants.

Salmon fibrin glue in rats: antibody studies. Anterior Cruciate Ligament deficiency leads to early instability of scaffold for cartilage regeneration: a controlled laboratory ex-vivo study. International Orthopaedics. Determination of porcine fibrinogen in rat and dog plasma after intraperitoneal injection of a porcine-derived fibrin glue by fluorescein-labeled assay method: comparison with isotope-labeled assay method. Journal of Pharmaceutical and Biomedical Analysis.

High thrombin concentrations in fibrin sealants induce apoptosis in human keratinocytes. Journal of Biomedical Materials Research A. Fibrinolytic proteins in human bile accelerate lysis of plasma clots and induce breakdown of fibrin sealants.

Composition of fibrin glues significantly influences axial vascularization and degradation in isolation chamber model. Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Fibrin glue is a candidate scaffold for long-term therapeutic protein expression in spontaneously differentiated adipocytes in vitro.

Experimental Cell Research. Effect of scaffold dilution on migration of mesenchymal stem cells from fibrin hydrogels. American Journal of Veterinary Research. Human adipose stromal vascular cell delivery in a fibrin spray. Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine.

In vitro and in vivo osteogenesis of human mesenchymal stem cells derived from skin, bone marrow and dental follicle tissues.

Vascular endothelial growth factor and fibroblast growth factor-2 incorporation in starch-based bone tissue-engineered constructs promote the in vivo expression of neovascularization mediators. Tissue Engineering A. Inflammatory response of intervertebral disc cells is reduced by fibrin sealant scaffold in vitro. Journal of Tissue Engineering and Regenerative Medicine. Injectable calcium phosphate cement and fibrin sealant recombined human bone morphogenetic protein-2 composite in vertebroplasty: an animal study.

Bosnian Journal of Basic Medical Sciences. The effect of bone morphogenetic protein-2 and osteoprotegerin in trans-sutural distraction osteogenesis.

Vertical bone augmentation with simultaneous implant placement using particulate mineralized bone and mesenchymal stem cells: a preliminary study in rabbit. Journal of Oral Implantology. Annals of the New York Academy of Sciences.

Effect of cultured autologous oral keratinocyte suspension in fibrin glue on oral wound healing in rabbits. International Journal of Oral and Maxillofacial Surgery. Fibrin gel as alternative scaffold for respiratory tissue engineering.

Annals of Biomedical Engineering. Polylactic-co-glycolic acid mesh coated with fibrin or collagen and biological adhesive substance as a prefabricated, degradable, biocompatible, and functional scaffold for regeneration of the urinary bladder wall. Comparative evaluation of suture-assisted and fibrin glue—assisted scleral fixated intraocular lens implantation. Journal of Refractive Surgery. Glued intrascleral fixation of posterior chamber intraocular lens in children.

American Journal of Ophthalmology. Intrascleral fibrin glue intraocular lens fixation combined with Descemet-stripping automated endothelial keratoplasty or penetrating keratoplasty. Glued endocapsular hemi-ring segment for fibrin glue-assisted sutureless transscleral fixation of the capsular bag in subluxated cataracts and intraocular lenses.

Journal of Cataract and Refractive Surgery. Fibrin glue-assisted fixation of decentered posterior chamber intraocular lens. Eye and Contact Lens. Effect of fibrin glue on the biomechanical properties of human Descemet's membrane. PLoS One. The use of fibrin glue to seal descemet membrane microperforations occurring during deep anterior lamellar keratoplasty. Our experience of fibrin sealant-assisted implantation of Ahmed glaucoma valve.

Indian Journal of Ophthalmology. Scleral fistula closure at the time of glaucoma drainage device tube repositioning: a novel technique. Archives of Ophthalmology.

Childhood pterygium: a descriptive study of 19 cases presented to a tertiary eye care center. Conjunctival autografting without fibrin glue or sutures for pterygium surgery. Conjunctival limbal autograft and allograft transplantation using fibrin glue. Ophthalmic Surgery Lasers and Imaging. Use of a fibrin adhesive for conjunctival closure in trabeculectomy. Acta Ophthalmologica. Small-incision, sutureless repair of subconjunctival fat prolapse.

Ophthalmic Plastic and Reconstructive Surgery. Safety and efficacy of fibrin glue versus vicryl sutures in recurrent pterygium with amniotic membrane grafting. Ophthalmic Research. Treatment of a large corneal perforation with a multilayer of amniotic membrane and TachoSil.

He L, Manche EE. Fibrin glue for prevention of recurrent epithelial ingrowth under a LASIK flap with a central buttonhole defect. Paste-pinch-cut conjunctivoplasty: subconjunctival fibrin sealant injection in the repair of conjunctivochalasis. Beneficial effects of fibrin glue Quixil versus Lichtenstein conventional technique in inguinal hernia repair: a randomized clinical trial.

Reducing postoperative pain: the use of Tisseel for mesh fixation in inguinal hernia repair. Surgical Technology International.

Comparing sutures and human fibrin glue for mesh fixation during open inguinal hernioplasty. Annali Italiani di Chirurgia. In press. Hernioplasty in elderly high-risk adults: efficacy of fibrin glue. Journal of the American Geriatrics Society. Lichtenstein repair of inguinal hernia: fibrin glue or suture for mesh fixation? Influence of fibrin sealant in preventing postoperative seroma and normalizing the abdominal wall after laparoscopic repair of ventral hernia.

Analysis of adhesions resulted from mesh fixation with fibrin sealant and suture: experimental intraperitoneal model. Strategies to minimize adhesions to intraperitoneally placed mesh in laparoscopic ventral hernia repair. Journal of the Society of Laparoendoscopic Surgeons. Biomechanical properties of semi- synthetic glues for mesh fixation in endoscopic inguinal hernia repair.

The impact of atraumatic fibrin sealant vs. Clinical outcome and quality of life in consecutive laparoscopic totally extra-peritoneal TEP groin hernia repairs using fibrin glue Tisseel : a United Kingdom experience. Staple versus fibrin glue fixation in laparoscopic total extraperitoneal repair of inguinal hernia: a systematic review and meta-analysis.

Mesh fixation with fibrin sealant during endoscopic totally extraperitoneal inguinal hernia approach: a review of repairs. Berney CR. The Endoloop technique for the primary closure of direct inguinal hernia defect during the endoscopic totally extraperitoneal approach. Evaluation of fibrin sealant for biologic mesh fixation at the hiatus in a porcine model. A unique method for repairing intraoperative pulmonary air leakage with both polyglycolic acid sheets and fibrin glue.

Prevention of alveolar air leakage after video-assisted thoracic surgery: comparison of the efficacy of methods involving the use of fibrin glue. The Thoracic and Cardiovascular Surgeon.

Verification of early removal of the chest tube after absorbable mesh-based pneumostasis subsequent to video-assisted major lung resection for cancer. Use of fibrin glue in the treatment of pneumothorax in premature infant. Pediatrics International. Successful treatment by fibrin glue sealant for pneumothorax with chronic GVHD resistant to autologous blood patch pleurodesis. Internal Medicine.

Chylothorax after primary repair of esophageal atresia with tracheo-esophageal fistula: successful management by biological fibrin glue. Thoracoscopic surgical treatment for pleuroperitoneal communication. Interactive Cardiovascular and Thoracic Surgery.

Successful application of subcutaneous adipose tissue with fibrin glue in conservative treatment of tracheobronchial rupture. Iatrogenic tracheal rupture: bovine pericardial patch repair without flap reinforcement. Closure of bronchopleural fistula with porcine dermal collagen and fibrin glue in an infant. Successful non-standard approaches to massive hemoptysis in invasive pulmonary aspergillosis. Srpski Arhiv za Celokupno Lekarstvo.

Kambayashi T, Suzuki T. Eosinophilic pleural effusion possibly induced by fibrin sealant. Kyobu Geka. Adverse effects of fibrin sealants in thoracic surgery: the safety of a new fibrin sealant: multicentre, randomized, controlled, clinical trial. European Journal Cardio-Thoracic Surgery.

Evaluation of resorbable barriers for preventing surgical adhesions. Fertility and Sterility. Analysis of the kinetics of peritoneal adhesion formation in the rat and evaluation of potential antiadhesive agents.

Efficacy of quilting sutures and fibrin sealant together for prevention of seroma in extended latissimus dorsi flap donor sites. Archives of Plastic Surgery. Latissimus dorsi donor-site morbidity: the combination of quilting sutures and fibrin sealant reduce length of drain placement and seroma rate. Due to this tendency of plasmin to destroy the fibrin clot, an antifibrinolytic agent such as aminocaproic acid should be added to glue component II in order to retard clot lysis and thus stabilize the tissues to allow scar formation.

Another advantage of fibrin adhesive is its low predisposition to infection. The growth of staphylococci in blood clots is 10 times higher than in fibrin clots and times higher than in fibrin clots containing factor XIII 3. Biological adhesives are used in several surgical procedures: closure of the dura, hemostasis, surgery of the middle and inner ears, septoplasty, facial nerve grafting, cerebrospinal fluid leak sealing CSF leaks, grafting of skin and mucous membranes, fracture stabilization, plastic surgery, and vascular, cardiac, thoracic, urologic, digestive, and dental microsurgery.

The scope for its use is virtually unlimited, and the benefits are numerous 4,5,6,7,8. Fibrinogen can be precipitated by various methods. Precipitation by the addition of a saturated solution of ammonium sulfate produces greater amounts of fibrinogen in a non-selective manner and brings down some additional proteins that are important in the clotting process 9.

In our study, autologous fibrin glues produced by 3 different methods formed clots identically well; however, skin grafting was equally successful when plasma cryoprecipitate or chemoprecipitate was used but unsuccessful when plasma precipitate was used. The 3 methods were equally satisfactory with respect to local toxicity, as the rabbits' sclerae showed no signs of injury.

Laboratory testing of the adhesion of dura mater fragments showed the worst results for glue produced from pure plasma, followed by that made from cryoprecipitate, while the best adhesion was obtained using chemoprecipitated plasma.

Although the adhesion of fibrin glue produced by chemoprecipitation was inferior to that of the commercial glue in the first 10 minutes, it has greater adhesiveness after 30 minutes Siendentop, and would therefore be preferable in situations in which the fragments are not subjected to large shifts. Based on our results, fibrinogen prepared by chemoprecipitation from plasma is better for surgical use than that prepared by the other 2 methods.

Some surgeons now utilize the patient's own blood to prepare fibrin glue for the surgical site; this is both less expensive and more convenient for the patient than using commercial glue.

Furthermore, the patient's own blood poses none of the risks for contamination or infection associated with the use of blood from blood banks and also minimizes the risk for allergic reactions. It is important to remember that the use of any biological or synthetic glue is no substitute for proper surgical technique. Fibrin glues produced by standard centrifugation, cryoprecipitation, and chemoprecipitation performed equally well at clot formation, and no method produced signs of toxicity in rabbit sclerae.

However, the adhesiveness and perioperative graft healing were poor for the glue produced by centrifugation alone. Plasma chemoprecipitation produced the best results for tensile strength testing of adhesion between dural fragments. We therefore conclude that chemoprecipitation is the most effective method for preparing fibrin tissue adhesive. Utilization of the commercial product surpassed use of the blood bank product in April At present, use of the commercial product is approximately 3 times that of the blood bank—produced sealant.

This report reviews the clinical uses of fibrin sealant, its regulatory history, the production of fibrin sealants, the evolution of a blood bank fibrin sealant program, the development of the Tissue Adhesive Center, and the utilization of commercial and blood bank—produced sealant at our university hospital.

Fibrin sealant tissue adhesives have become an important and versatile tool in the surgical armamentarium over the past 30 years, with applications ranging from improving hemostasis and sealing tissues to targeted delivery of drugs. Composed primarily of fibrinogen and thrombin, fibrin sealant acts by mimicking the final stage of the natural clotting mechanism to form a fibrin clot that is broken down by fibrinolysis and reabsorbed naturally over the course of several days.

The process by which fibrinogen and thrombin combine in the presence of Factor XIII and calcium chloride to form a fibrin clot has been well described [ 1 — 3 ]. Fibrin sealant has three primary applications: It can be used as a hemostat, as a sealing agent, and as a carrier mechanism for delivering drugs and other bioactive agents such as growth factors to targeted sites in the body. In the s, Young and Medawar [ 7 ] reported the use of fibrinogen to repair severed nerves in animal models.

However, it was Cronkite et al [ 8 ] and Tidrick et al [ 9 ] who, in , first combined fibrinogen and thrombin to form fibrin sealant for anchoring skin grafts. These early forms of fibrin sealant lacked adhesive strength due to their low fibrinogen concentrations. It was not until the s that interest was rekindled, owing to the implementation of industrial plasma fractionation methods that allowed the production of a more concentrated form of fibrinogen [ 10 ].

Currently, fibrin sealant is used in virtually every surgical specialty [ 11 ]. The primary area of usage is cardiovascular surgery, where applications include sealing of complex suture lines, vascular conduits, cannulation sites, and vascular anastomoses [ 12 , 13 ]. Fibrin sealant has been used in cardiovascular surgery in conjunction with polytetrafluoroethylene patches [ 17 ], polytetrafluoroethylene bypass grafts [ 16 ], woven Dacron grafts [ 18 ], and pericardial patches [ 19 ].

In pulmonary thoracic surgery, fibrin sealant helps to seal air leaks [ 20 ] and close bronchopleural fistulas [ 21 , 22 ], as well as reinforce suture or staple lines after thoracotomy or lung resection [ 23 ]. One review of clinical studies of fibrin sealant in cardiac and thoracic surgery noted that, through , none of the 24 published controlled clinical studies had demonstrated a deleterious effect from use of fibrin sealant, either in terms of efficacy inferior to controls or serious adverse events [ 24 ].

However, the potential for adverse reactions, such as coagulopathy associated with the bovine thrombin present in some noncommercial fibrin sealant formulations, suggests that fibrin sealant containing human rather than bovine thrombin may be preferable.

In neurosurgery, fibrin sealant has commonly been used as an adjunct to dural closures, to reduce postoperative cerebral spinal fluid leakage [ 25 , 26 ], and in the repair of dural defects [ 27 ]. Additional applications include microvascular decompression, laminectomy, tumor resection via craniotomy, myelomeningo-cele repair, rhizotomy, and arteriovenous malformation repair.

In plastic surgery, fibrin sealant has been especially effective in controlling bleeding following burn debridement [ 28 ] and as an adjunct to maxillo-facial [ 29 ] and head and neck surgery [ 25 , 30 ]. Used as an adjunct to mandibular reconstruction along with cancellous bone and marrow, fibrin sealant has been noted to accelerate revascularization and migration of fibroblasts, thereby stimulating healing and growth.

Fibrin sealant is effective in sealing dead spaces left after surgical excision as in axillary dissection , where there is a potential for serous drainage leading to seroma formation [ 36 ], and has been shown to reduce seroma formation following radical neck dissection [ 34 ] or breast surgery with axillary dissection [ 35 ].

Otolaryngology, otology, and neurotology are other fields in which fibrin sealant has been widely used [ 25 , 37 — 39 ], with applications in sinus surgery [ 40 ], tonsillectomy [ 41 , 42 ], tympanoplasty [ 43 ], and, potentially, other forms of ear surgery [ 44 — 46 ]. In general surgery, fibrin sealant is used to achieve hemostasis on raw surfaces of the liver and in reconstruction of the spleen, especially following traumatic injury [ 47 , 48 ].

The planned introduction of a fibrin sealant bandage and dry fibrin sealant formulations may provide new treatment alternatives for trauma patients [ 49 ].

Fibrin sealant has proved valuable for sealing colon anastomoses one of its current FDA—approved indications. There may be significant potential for reduced-suture and sutureless anastomosis using fibrin sealant [ 50 ].

There are other documented applications of fibrin sealant in orthopaedic, ophthalmologic, trauma, head and neck, gynecologic, urologic, gastrointestinal, and dental surgery [ 11 ].

Recent reviews have documented a wide variety of surgical settings in which fibrin sealant has proved valuable, such as promoting hemostasis in patients who have coagulation disorders [ 51 ] or are receiving anticoagulant therapy, or to promote the closing of rectovaginal, perirectal, and other fistulas [ 52 ].

The future of fibrin sealant extends beyond hemostasis and sealing. Its ability to act as an effective delivery medium for growth factors and antibiotics in order to promote healing is receiving growing attention [ 53 — 56 ]. Fibrin sealant may also prove to be an adjunct to minimally invasive surgery eg, laparoscopic and endoscopic procedures [ 57 — 59 ].

Although commercial fibrin sealant made from pooled plasma—derived human fibrinogen and human thrombin has been available in Europe, Canada, and Japan for several years since in Europe , the US Food and Drug Administration FDA did not approve the commercial product for use in the USA until May Delay in availability of commercial fibrin sealant in the USA was largely due to concerns over possible viral disease transmission from blood-borne pathogens such as HIV, hepatitis B virus, and hepatitis C virus.

In fact, approval for use of commercial fibrinogen derived from pooled plasma was withdrawn in the USA in due to concern over virus transmission [ 60 ]. Currently, licensed commercial sealants contain fibrinogen and thrombin derived from pooled, virally inactivated human plasma.

They also contain an antifibrinolytic agent, bovine aprotinin. Future generations of fibrin sealant are likely to be free of bovine products due to reported instances albeit rare of reactions to bovine aprotinin [ 61 ].

As increasingly sensitive virus detection techniques become available [ 63 ], shortening or even closing the window for infectious donations, and as improved virus inactivation techniques are developed, such as solvent detergent cleansing [ 64 ], general acceptance of products derived from pooled plasma may grow. In fact, pooled, virus-inactivated blood products have been shown to be very safe [ 65 ].

Furthermore, recombinant fibrinogen and thrombin are likely to become available, thereby eliminating the viral disease risk [ 66 ]. Despite the lack of approved commercial fibrin sealant, surgeons in the USA explored applications of this adhesive throughout the s and s, using fibrin sealants produced locally from autologous or allogeneic single-donor blood.

Even with the current availability of commercial fibrin sealant, some institutions, including the University of Virginia, continue to make their own fibrin sealant, particularly for autologous use, due to continued concerns over the cost, and, to a lesser extent, safety of commercial preparations.

The concentrated fibrinogen produced by these various methods, or from standard cryoprecipitate, is then combined with topical bovine thrombin, and occasionally an antifibrinolytic agent such as aprotinin, tranexamic acid, or epsilon aminocaproic acid to slow fibrinolysis of the fibrin clot [ 67 ]. Because thrombin concentration is directly related to the rate of polymerization of fibrin, studies have been conducted to determine the ideal ratios and concentrations of thrombin and fibrinogen [ 68 , 69 ].

Concerns about safety of bovine thrombin have been raised due to reports of adverse reactions, which include hypotension, anaphylactic shock, and coagulopathy [ 70 ]. Although infrequent, the occurrence of adverse reactions to bovine thrombin underscores the need for vigilance in the use of topical bovine thrombin and the importance of identifying patients with previous exposure to this product.

Such patients appear 8-times more likely to develop antibodies than patients exposed for the first time [ 71 ]. While safety concerns have occasionally been raised about commercial fibrin sealant, due to its pooled-plasma origin, the fact that the commercial product contains human rather than bovine thrombin makes it relatively safer than blood-bank fibrin sealant for patients with previous exposure to bovine thrombin.

However, as noted above, the licensed commercial preparations contain bovine aprotinin, which may produce adverse reactions in rare instances. The term cryoprecipitate is used loosely in the literature and may refer to a the FDA—licensed product Cryoprecipitated AHF anti-hemophilic factor , used to treat Factor VIII deficiency and deficiencies of von Willebrand Factor, fibrinogen, and Factor XIII, or b cryoprecipitated plasma made by individual institutions by approximately the same methods, with institutional variations.

Whole plasma has also been used as a source of fibrinogen in fibrin sealant [ 72 ]. Since it appears that the bonding strength of the adhesive is directly related to the fibrinogen concentration, cryoprecipitate is considered a more desirable source of the fibrinogen component of fibrin sealant than whole plasma.

These methods have the advantage of not requiring advance planning; however, as with fresh frozen plasma, unless the plasma collected is subjected to further processing in order to increase fibrinogen concentrations, it tends to be less viscous and to have a lower bonding strength than cryoprecipitated plasma [ 79 ]. It has been argued, however, that whole, fresh, citrated plasma fractionated from autologous blood is as effective as cryoprecipitate as a hemostatic agent [ 72 ].

Methods for making concentrated fibrinogen for use in fibrin sealant from small volumes of blood drawn peri-operatively have also been described [ 81 , 82 ], which allow rapid production and volume customization for applications that only require small amounts of fibrin sealant. Not only have multiple sources of plasma been used in making fibrin sealant, but various methods have been employed to process the plasma obtained by these sources to enhance the concentration and yield of fibrinogen beyond those achieved by standard cryoprecipitation methods, and to shorten processing time [ 83 ].

While the foregoing methods all appear to enhance fibrinogen yield and concentration, there is no consensus about which one gives the highest fibrinogen concentration. Several studies have identified ammonium sulfate precipitation as yielding a higher fibrinogen concentration and therefore greater bonding strength than standard cryoprecipitation or precipitation with ethanol or polyethylene glycol [ 89 — 91 ], but other studies have failed to confirm these findings [ 92 , 93 ].

Variations in yields and concentrations of fibrinogen obtained by these various methods are not surprising, given the variations in a donor blood fibrinogen levels, b concentrations and volumes of precipitating agent used 87 , and c methods and parameters used to measure bonding power 91 , Regardless of the processing method, the final fibrinogen concentrations are directly related to fibrinogen concentrations in the donated blood Although precipitation with exogenous agents may shorten the time required for obtaining fibrinogen concentrate from plasma, the potential risks involved with use of such agents in the cryoprecipitation process have not been fully elucidated.

For instance, the ethanol method can lead to elevated alcohol concentrations in the product, which may cause premature clotting of fibrinogen [ 96 ] and reduced Factor XIII activity [ 1 ]. By varying the amount of supernatant, the blood bank can customize the volume and fibrinogen concentration. Commercial fibrin sealant preparations with high fibrinogen concentrations produce sealant with increased strength, but in locally-produced products, thrombin concentrations can be adjusted to manipulate the rate of sealant formation.

In plastic surgery procedures this may be especially advantageous, as reduced thrombin concentrations in the sealant give the surgeon more time to manipulate the tissues. Until , investigations in the USA of potential uses for fibrin sealant depended largely upon collaboration with hospital clinical laboratories and local blood banks. Such a program was developed in at the University of Virginia UVA ; the surgical services and the blood bank collaborated to make fibrin sealant for clinical use within the University of Virginia Health System [ 98 ].

The Center has a core staff of nurses, a physician director, and administrative staff. Relationships among the UVA Blood Bank, the Center, and the surgical services have provided unique opportunities for collaboration and have resulted in tracking and peer review of fibrin sealant use at UVA, identification of educational needs and development of in-service programs, and preclinical and clinical fibrin sealant trials [ 41 , 99 , ].

The evolution of fibrin sealant experience and use at UVA shows how blood bank—produced and commercial fibrin sealant can enhance and promote each other. Concerns about cost containment and effective blood product usage have led to the development of a method for preparing fibrin sealant from novel sources, such as outdated fresh frozen plasma and plasma that has been thawed but not used within the time stipulated by blood bank policies [ ].

Although use of single-donor units of plasma that have been tested for viral disease markers can greatly reduce the risk of virus transmission, the only way to eliminate this risk is to use autologous blood for preparing the fibrinogen component of fibrin sealant.

The only other risk that has been associated with topical application of fibrinogen concentrate from allogeneic blood is the occurrence of a systemic allergic reaction caused by antibodies to IgA [ ]. The challenges in implementing this program included addressing different time frames established for collecting blood for various surgical procedures, coordinating regional donations at outlying centers for patients, facilitating red blood cell reinfusion where necessary, accommodating variations in the volume of product required, and maintaining sterility.

Development of a rapid method for preparing fibrinogen from a small volume of blood collected prior to surgery avoided delays in producing autologous fibrinogen from whole blood and facilitated the production of fibrin sealant for selected applications, eg, closing bleb leaks after glaucoma filtration surgery [ 81 ].

However, care must be taken that such blood is carefully handled to maintain sterility and safety of the product. The common practice has been to collect autologous whole blood in the weeks prior to surgery. This has facilitated the production of an additional safe and effective patient care product—autologous fibrinogen concentrate—that can be used to make fibrin sealant at little additional cost, without compromising the autologous red blood cell component.

Patients have been receptive to the concept of enhancing their care by participation in the autologous fibrinogen program. Patients have participated even when sealant was the only autologous component needed for their surgery.

The autologous fibrinogen program, while more labor intensive and time-consuming than the stored plasma method, results in a relatively cost-effective product.

Use of fibrin sealant may result in reduced need for post-operative transfusions of allogeneic blood [ ], and the costs of preparing the adhesive may be offset by the savings in this regard.

At UVA, autologous fibrinogen concentrate is prepared in the blood bank from whole blood collected by our blood supplier. The blood center collects and provides whole blood whether or not the physician anticipates a need for autologous red blood cells. The blood bank does not have other requests for this plasma. Unlike autologous concentrate, the allogeneic product does not require separation from whole blood and subsequent freezing and requires less recordkeeping than preparing autologous concentrate.

Tracking fibrin sealant utilization at UVA from autologous and single-donor units of blood over the period — showed that demand grew from units in to units in