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Osseous Regeneration in the Presence of Fibrin Adhesive Material (Tissucol®) and Epsilon-Aminocaproic Acid (EACA)

Tetuo OKAMOTO[1]
Maria Cristina R. ALVES-REZENDE[2]
Ana Cláudia OKAMOTO[1]
Idelmo R. GARCIA Jr.[1]
[1]Disciplina de Cirurgia e Traumatologia Buco-Maxilo-Facial and
[2]Disciplina de Materiais Odontológicos, Faculdade de Odontologia, UNESP, Araçatuba, SP, Brasil

Braz Dent J (1995) 6(2): 77-83 ISSN 0103-6440

| Introduction | Material/Methods | Results | One day after surgery | Three days after surgery | Seven days after surgery | Fourteen days after surgery | Twenty-one days after surgery | Discussion | Conclusions | References |

The effects of Tissucol® and Tissucol®/EACA on bone healing were evaluated histologically. Experimental defects were made in both tibias of 25 rats. Test materials were placed in defects in right tibias and left tibias served as control. Five animals in each group were killed at 1, 3, 7, 14 and 21 days after surgery. Results showed that: a) Tissucol® did not interfere with connective and osseous tissue formation; b) Tissucol® allowed new bone formation; c) Tissucol® residues in Tissucol® groups in sections of 21-day specimens did not impair healing; d) Tissucol®/EACA was usually completely resorbed and healing was complete 21 days after surgery in the Tissucol®/EACA group.

Key words: fibrin sealing, epsilon-aminocaproic acid, bone healing.


The effectiveness of hemostatic agents is characterized by their ability to allow bone regeneration and to undergo resorption.

Studies evaluating the effects of fibrin adhesive material (Tissucol®) in surgical sites have generally found it to be an effective agent in maintaining a dry field and allowing new bone formation (Baldin et al., 1985; Palattella et al., 1985). In addition, results of some experimental (Alves-Rezende and Okamoto, 1992, 1995; Okamoto et al., 1995) and clinical studies (Matras, 1982; Wepner et al., 1982; Caruso et al., 1984; Stajicic et al., 1985) suggested that resorption of Tissucol® occurred in the presence of tissue formation.

Alves-Rezende and Okamoto (1995) reported positive results with the use of epsilon-aminocaproic acid (EACA) before using the fibrin tissue adhesive (Tissucol®). They compared Tissucol® and Tissucol®/EACA as hemostatic agents on alveolar cavity in rats under stress and observed complete healing in a 24-day period with Tissucol®/EACA. Furthermore, Tissucol®/EACA showed better resorption than Tissucol® under similar conditions.

Okamoto et al. (1995) evaluated the effects of Tissucol® on bone healing in rat tibias and observed small fragments of material 21 days after implantation. However, they reported that the healing of the experimental defects was qualitatively similar to those observed in control defects.

Therefore, the present study was designed to evaluate the effects of fibrin tissue adhesive (Tissucol®) with epsilon-aminocaproic acid (EACA) on osseous healing in rat tibias.

Material and Methods

Twenty-five male albino (Rattus norvegicus albinus, Wistar) weighing 300 to 350 g were employed. They were fed a diet of standard Purina rat chow and water ad libitum. At surgery, each animal was anesthetized by intraperitoneal injection of thionembutal (50 mg/kg body weight). The incision site was cleaned with 70% ethanol and a 2-3 cm incision was extended distally from the tibial tubercle. The medial surface of each tibia was exposed and an opening (one on left tibia and two on right tibia) that extended through the cortex into the medullary cavity was made in the middle of each surface 5 mm distal to the tibial tubercle with a slow-speed handpiece and # 8 burr. A hemostatic agent was placed in the defects in the tibias of each animal in the following manner. In the right tibia, Tissucol® (Immuno A.G., Vienna) was inserted in the upper defect after it was mixed according to the manufacturer's directions. The lower defect was irrigated with epsilon-aminocaproic acid (EACA) (5 ml of 5% solution for 2 min) before implanting Tissucol®. The defect of the left tibia served as an empty control. Incisions were closed with 4-0 gut sutures placed 3 mm apart. Five animals were killed by ether overdose at 1, 3, 7, 14 and 21 days after surgery. Appropriate areas of the tibias were isolated by gross dissection and placed in 10% formaldeyde. Following fixation, the specimens were decalcified in a 15% formic acid solution and processed for routine paraffin embedding. Seven-micrometer sections were cut and stained with hematoxylin and eosin. All sections were examined with a Zeiss universal microscope.


One day after surgery

The osseous defects were filled with fibrin clot and an influx of inflammatory cells was seen. In Tissucol® specimens there were neutrophils adjacent to the test material which occupied a larger portion of the osseous defect. Some macrophages were observed permeating the fibrin clot, which were more pronounced in the Tissucol®/EACA specimens and control specimens than in Tissucol® specimens. In the control sites and Tissucol®/EACA sites more new budding capillaries and fibroblasts were noted.

Three days after surgery

The osseous defects were filled with an organized fibrin clot which showed more macrophagic invasion in the Tissucol®/EACA group and control group than in the Tissucol® group. The test implant was observed in the center of the defect and there were signs of resorption in Tissucol®/EACA sites. Fibroblast proliferation was scattered throughout the implant in Tissucol®/EACA specimens.

Seven days after surgery

Tissucol® and Tissucol®/EACA implant sites showed residual masses of test material (Figure 1A,B). The implant material was surrounded by peripheral fibrous connective tissue and there were small amounts of new bone scattered around the periphery in Tissucol®/EACA specimens. In the control group, active bone formation was noted throughout the control defects (Figure 1C).

Figure 1 - A, A 7-day Tissucol® specimen demonstrates a residual mass of material (M) (hematoxylin and eosin, original magnification X160). B, A 7-day Tissucol®/EACA specimen demonstrates a residual mass of Tissucol®/EACA (T®/E) surroun-ded by immature bony trabeculae (T) (hematoxylin and eosin, original magnification X160). C, A 7-day control specimen demonstrates active bone forma-tion in the center of the osseous defect (hematoxylin and eosin, original magnification X160).

Fourteen days after surgery

A thicker trabeculae of immature bone occupied most of the defect in the control group. In the Tissucol® group, occasional material remnants were observed which were surrounded by immature bony trabeculae or fibrous connective tissue. In Tissucol®/EACA specimens, a dense trabeculae of bone was observed in most of the defect. Some specimens showed residual masses of material while other specimens showed no material.

Twenty-one days after surgery

In the control group, the defect was filled by remodeling compact bone that was delineated from older bone by cement lines (Figure 2A). Bone regeneration was complete. In the Tissucol® group, the specimens showed more bone repair compared with 14-days. Residual masses of material were still present (Figure 2B). Tissucol®/EACA specimens demonstrated a substantial increase in the amount of mature bone (Figure 2C). There was no material found in any of the specimens.

Figure 2 - A, A 21-day control specimen demonstrates cement lines (L) demarcating newly formed bone (nb) from surround-ing unmanipulated cortical bone (B) (hematoxylin and eosin, original magnification X160). B, A 21-day Tissucol® specimen demonstrates a residual mass of the material (M) surrounded by immautre bony trabeculae (T) (hematoxylin and eosin, original magnification X160). C, A 21-day Tissucol®/EACA specimen demonstrates the large amount of dense bone trabeculae filling the experimental defect (hema-toxylin and eosin, original magnification X160).


The healing of control defects in rat tibias was similar to that described by other investigators (Howard and Kelley, 1969; Ligget et al., 1980; Ibarrolla et al., 1985; Haasch et al., 1989).

The most significant finding of this study was the beneficial effect of epsilon-aminocaproic acid (EACA) on resorption of Tissucol®. As noted in other studies there is a greater probability of resorption of Tissucol® in the presence of EACA.

In a comparative study of Tissucol® and Tissucol®/EACA, Alves-Rezende and Okamoto (1995) emphasize the importance of irrigation procedures with EACA before implant of Tissucol®. We agree that careful irrigation with EACA before implant of this material is necessary regardless of the implant site.

Tissucol® did not cause any untoward reactions when placed in bone defects. Organization and osteogenesis were observed 14 days after implantation, which is comparable to events observed in controls. Small fragments of the material were observed in sections of 21-day specimens but did not cause inflammation or impair healing.

When EACA was used before implant of Tissucol®, it resorbed more rapidly and there was little resistance to resorption, even when placed in volumes greater than actually needed to control bleeding at the surgical sites.

Based on the findings, we believe that Tissucol® and Tissucol®/EACA should be used as a hemostatic agent in surgical procedures.


In this study, both Tissucol® and Tissucol®/EACA were effective hemostatic agents. Tissucol® and Tissucol®/EACA did not elicit foreign body reaction and did not prevent bone healing. The irrigation procedures with epsilon-aminocaproic acid (EACA) solution before implant of the Tissucol® facilitated the resorption of the material.


This work was supported by FAPESP.


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Okamoto T, Alves-Rezende MCR, Buscariolo IA, Okamoto AC, Garcia IR: The effect of fibrin adhesive material (Tissucol) on the healing of experimental rat tibial lesions. Rev Odont UNESP (In press) Palattella G, Massi C, Corbeli V, Ruggeri B, Pignatelli N, Palattella E: L'impiego della colla di fibrina umana liofilizzata "Tissucol" nella chirurgia orale. Dental Cadmos 53: 65-68, 1985

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Correspondence: Prof. Dr. Tetuo Okamoto, Disciplina de Cirurgia e Traumatologia Buco-Maxilo-Facial, Faculdade de Odontologia, UNESP, Rua José Bonifácio, 1193, Caixa Postal 533, 16015-050 Araçatuba, SP, Brasil. © 1999 - 2002, Todos os direitos reservados.
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