Epsilon Aminocarporit Acid

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Okamoto T, Alves-Rezende MCR, Cludio CC, Rodrigues TS, Okamoto R. Effects of tissucol and epsilon aminocaproic acid in thehealing process following dental extraction in dehydrated rats. Braz Oral Res 2006;20(1):33-9.

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basic conditions to guide the healing of the dentalsocket 1 .

During blood coagulation, extrinsic and in-trinsic mechanisms activate prothrombin intothrombin and, in the presence of Ca ++ , producethe hydrolysis of fibrinogen into fibrin, bound withhydrogen bridges, and also activate coagulationfactor XIII, a beta-globulin present in plasma inan active form. Factor XIII, a fibrin-stabilizing fac-tor initially described by Laki, Lorand 10 (1948), isresponsible for the cross reactions formed betweenfibrin monomers (producing the fibrin screen, thatfacilitates the growth of fibroblasts) and betweencollagen and fibrin 7 . Beck et al .2 (1961) showedthat there is no fibroblastic growth in the absenceof factor XIII.

Cabrera et al .4 (1988), studying the negative

hydric balance effects on alveolar bone healingfollowing tooth extraction, observed that the de-crease in liquid ingestion produced a significantreduction in the vascularization of alveolar tissues,changes in the morphology of the healing processand a delay in the temporal evolution of the many healing stages.

The dehydration produces a decrease in theplasmatic and corpuscular volume, increasing thehematocrite and plasmatic protein levels 2,11 , pro-ducing an increase in the blood viscosity. Cabrera-Peralta et al .5 (1982) considered that these factors

may determine the decrease or the blockade of the changes of substances through the capillary membrane, affecting cellular activity and changingthe healing tissue formation process.

It seems, therefore, that the use of substancesthat maximize the physiological healing processcould change the fibrinolytic conditions producedby dehydration. The adhesive system Tissucol ,basically composed of fibrinogen, aprotinine, fac-tor XIII and thrombin has been used in surgeriesas a tissue adhesive, and primarily has contributedin hard and soft tissues haemostasis in the oralcavity and in many clinical situations, when thefibrinolytic system is in prejudice 13 .

Alves-Rezende, Okamoto 1 (1997) studied thealveolar bone healing in rats after Tissucol im-plantation and observed that the material wasslowly phagocityzed during this process, whichwas not complete at the 21 st postoperative day.

They observed that connective and bone tissueswere formed closely to the material, indicating itsbiocompatibility. Staindl 25 (1979) recommendedthe previous irrigation of the wound with Epsilonaminocaproic acid (EACA) before Tissucol im-

plantation, with the aim to increase its biologicalproperties.

Considering these data, the present study aimed to evaluate the alveolar bone healing processin dehydrated rats, after Tissucol implantationassociated to previous irrigation of the extractionsocket with 5% EACA.

MATERIAL AND METHODS

To perform this study, 72 male rats ( Rattus nor- vegicus , Wistar) were used. The 220-250 g weightanimals were anesthetized with Sodic Tionembu-tal (Abbott, Abbott Park, IL), with a 50 mg/kg of weight dosage. After syndesmotomy, the right up-per incisor of each animal was extracted, using aspecially adapted instrument 20 .

The 72 rats were divided into 3 groups: Group I:Control; Group II: Dehydrated rats; Group III: De-hydrated rats that received the Tissucol implant(Osterreichisches Institute fur Haemoderivate GesM.B.H., Immuno Produtos, Rio de Janeiro, Bra-zil) associated to previous irrigation of the dentalsocket with 5% EACA (Qumica Farmacutica Nik-kho do Brasil, Rio de Janeiro, Brazil).

The chronic dehydration of the experimen-tal rats was produced by water deprivation, thatlasted 9 days, considering that 3 days were duringthe preoperative period and 6 days were during the

postoperative period. The animals were separatedin individual cages and maintained in a tempera-ture of 30 C 2 C. They received food and waterad libitum, except for 24 hours after surgery. Therats of Groups II and III were rehydrated in thesixth postoperative day with free access to water.

Immediately after extraction in groups I andII, the wounds were sutured with polyglactine 910thread (Vycril, 4.0, Ehicon, So Jos dos Campos,Brazil). In group III, the extraction sockets receivedirrigation with a 5% EACA solution, followed by

Tissucol implantation. After this, the wound wassutured in a similar way as in groups I and II.

Six animals from the groups were sacrificedat 3, 7, 15 and 21 postoperative days. The rightupper jaw was removed and fixed in a 10% forma-lin solution for 24 hours and decalcified for a pe-riod of 30 days in a solution of sodium citrate andformic acid in equal parts 15 . After decalcification,the specimens were washed during 24 hours anddehydrated, diafanized and imbedded in paraffin.

The longitudinal semi-serial slices were obtainedwith 6 m in thickness and were stained with he-matoxylin and eosin.


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FIGURE 3 - G. III, 7 days: Middle third of the extractionsocket showing the lingual side with thin bone tra-beculae (HE, 63 X).

FIGURE 4 - G. II, 15 days: Middle third of the extractionsocket, with the lingual side showing isolated smallspikes (HE, 63 X).

FIGURE 5 - G. III, 15 days: Middle third of the extrac-tion socket, with the lingual side showing thin bonetrabeculae with numerous osteoblasts on their borders(HE, 63 X).

FIGURE 6 - G. I, 21 days: Middle third of the extractionsocket showing bone trabeculae (HE, 63 X).

served. Next to the middle and apical thirds, moredeveloped bone trabeculae were noted, usually next to the bone alveolar wall. Numerous osteo-blasts could be observed on their border.

Group II (15 days) On all of the extensionof the extraction socket, small areas occupied withblood clot without organization were observed,showing a discrete number of macrophages andlymphocytes. Connective tissue showing a discretenumber of fibroblasts was noted. In many points,this tissue showed little vascularization and, at themiddle and apical thirds, small bone spikes wereobserved, with a discrete number of osteoblastson their border (Figure 4).

Group III (15 days) The extraction socket,except for some points occupied with blood clot,

was filled with neoformed connective tissue, show-ing different characteristics. Next to the cervicalthird, the ossification was discrete and isolatedbone trabeculae were noted, with numerous osteo-blasts on their borders. At the middle and apicalthirds, the bone trabeculae were more developed;otherwise, in some points they were thin, withlarge intertrabecular spaces (Figure 5).

Groups I, II and III (21 days) At the threethirds of the dental socket, the presence of neo-formed bone trabeculae was observed. Comparedto the control group (Figure 6), the ossification wasless intense in Group II (Figure 7) than in Group III(Figure 8). Therefore, the bone trabeculae werethinner, showing greater amounts of connectivetissue without bone differentiation.


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FIGURE 7 - G. II, 21 days: Middle third of the extractionsocket showing fewer bone trabeculae with osteoblastson their border (HE, 63 X).

FIGURE 8 - G. III, 21 days: Middle third of the extrac-tion socket, showing well developed bone trabeculae(HE, 63 X).

DISCUSSION

Bergel 3 described the use of a fibrin sealantas a hemostat in 1909. In 1915, Grey 9 describedthe use of fibrin for haemostatic purposes dur-ing cerebral surgery. In 1940, Young, Medawar 26 described the use of fibrinogen as an adhesive toachieve peripheral nerve attachment. Cronkite et al .6 provided the first description of using bothfibrinogen and thrombin as a biologic glue for thepurposes of skin grafting in 1944. The use of afibrin sealant containing concentrated fibrinogenwas described for neural anastomoses in 1972 by Matras et al .14 (1972). In 1983, Gestring, Lerner 8 described clinically useful chemical and cryopre-cipitation methods for producing concentrated fi-brinogen for use in fibrin sealants.

Fibrin sealant has been used for enhance-ment of local haemostasis after dental extractionsfor over two decades. Fibrin sealing mimics thelast phase of blood clotting, i.e., the conversion of fibrinogen into fibrin 12 . During wound healing theclot material undergoes gradual lyses and is com-pletely absorbed within two weeks. Aside from itsadhesive and haemostatic properties, the sealanthas been found to enhance wound healing. Stud-ies comparing the effectiveness of fibrin sealantin patients undergoing dental extractions who aretherapeutically anticoagulated with warfarin haveshown equally successful outcomes with respectto haemostasis 23 .

Ycel et al . 27 (2003) encouraged the use of fibrin glue on wound healing in the oral cavity.

They reported the excellent results with the prod-uct in septic open wounds in the oral cavity. It

seems that one of the most significant pathogenicfactors for the development of bleeding after oralsurgery is the activation of fibrinolysis in the oralcavity. The literature suggests an advantage of using fibrin sealant at the time of dental extrac-tions in combination with antifibrinolytic agents.It appears to reduce bleeding at the time of dentalextractions in patients with coagulopathies fromhemophilia or therapeutic anticoagulation withwarfarin 21,22 . In 1989 a study by Sindet-Pedersenet al .24 demonstrated that the maintenance of oralanticoagulant therapy in conjunction with oralsurgery does not result in severe bleeding com-plications in patients receiving a tranexamic acidmouthwash postoperatively.

An animal study developed by Alves-Rezende,Okamoto 1 (1997) suggested that the biologicalproperties of Tissucol , increased in associationwith EACA, might have contributed to the dentalextraction wound healing in rats under stress.

These authors believed that Tissucol in associa-tion with EACA would be useful for haemostaticprocedures.

The biological compatibility of the applied ma-terial is increased when the surgical wounds arepreviously irrigated with EACA solution 1,17-19 . Theobtained results are in accordance with data of theliterature that describes the reversal of a fibrino-lytic state in the presence of Tissucol 1,16-18 .

Our results observed at postoperative days con-firm the tendency to healing changes in Group II,in great part reversed in Group III. The use of afibrin adhesive in Group III practically producedthe reversal of a fibrinolytic situation caused by dehydration. While the disorganized blood clot was


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evident in some specimens of Group II, until lateperiods of observation (21 days) in Group III, thepresence of Tissucol provided the fibrin screennecessary for fibroblastic aggregation and for thehealing process to evolve.

In face of the complexity of the events involvedin the healing of dental sockets, other researchesare necessary to assert the clinical use of fibrinadhesive in managing healing alterations in de-hydrated patients.

CONCLUSIONS

According to the experimental conditions fol-lowed in the present study, it is possible to con-clude that:

1. Water deprivation at the preoperative andpostoperative periods caused a delay in theconnective tissue neoformation in the dentalsocket healing process;

2. The use of the fibrin adhesive Tissucol pro-duced an improvement of the fibrinolytic situ-ation caused by dehydration.

ACKNOWLEDGEMENTS

We would like to thank Gilmar Martins deOliveira, Maria Dirce Colli Boatto and BernadeteMaria Nunes Kimura for their contribution in thehistological processing of the experiments in thisstudy.

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2. Beck E, Duckert F, Ernst M. The influence of fibrin stabiliz-ing factor on the growth of fibroblasts in vitro and woundhealing. Thromb Diath Haemorrh 1961;6:485-91.

3. Bergel S. Uber Wirkungen des Fibrins. Dtsch Med Wochen-schr 1909;35:633-65.

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17. Okamoto T, Alves-Rezende MCR, Buscariolo IA,Okamoto AC, Mendes VS, Garcia-Junior IR. Implante daassociao esponja de fibrina Fibrinol /adesivo fibrni-co (Tissucol ) em cavidade cirrgica preparada em tbiade rato. Estudo histolgico. Rev Odontol Univ So Paulo1996;10:33-7.

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cariolo IA, Garcia-Junior IR. The effect of fibrin sponge(Fibrinol ), fibrin adhesive (Tissucol ) and epsilon-aminoca-proic acid (EACA) on the healing of experimental rat tibiallesions. Rev Faculdade Odontol Lins 1997;10:12-5.

20. Okamoto T, Russo MC. Wound healing following toothextraction. Histochemical study in rats. Rev Fac OdontolAraatuba 1973;2:153-69.

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Larfars G, Nicol P et al . A comparison of six weeks with sixmonths of oral anticoagulant therapy after a first episodeof venous thromboembolism. Duration of anticoagulationtrial study group. N Engl J Med 1995;332:1661-5.

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27. Ycel EA, Oral O, Olgac V, Oral CK. Effects of fibr inglue on wound healing in oral cavity. J Dent 2003;31(8):569-75.

Received for publication on Jun 02, 2005Sent for alterations on Sep 26, 2005Accepted for publication on Jan 10, 2006

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yngol 1979;88:413-8.26. Young JZ, Medawar PB. Fibrin suture of peripheral

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Epsilon Aminocarporit Acid