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Oral surgery—oral pathology conference No. 22, Walter Reed Army Medical Center
Section
of the
Federal dental services Oral surgery-oral pathology conference
Con,ducted by Surindar N. Bhaskar, Colonel, DC, USA”
B
ecause of their adhesive and hemostatic properties, a family of compounds called the cyanoacrylates has received a great deal of attention. Although the methyl cyanoacrylate is histotoxicl? z and therefore unacceptable for clinical use, it has been shown in this laboratory that a number of other compounds of the cyanoacrylate family are well tolerated by the tissues.2y3 Of the available adhesives, the butyl cyanoacrylate has been the subject of most extensive investigation.4-g This material has been tested in the healing of soft-tissue and bone wounds in animals, and it has also been used as a surface dressing in a variety of surgical procedures on the oral soft tissues of man.2-9 In more than 600 applications in human patients it not only facilitated the healing process but also reduced the operative time, produced immediate hemostasis, and improved the patient’s comfort. 8,lo Biopsy specimens taken from surgical sites 21/2 years after application of this material failed to reveal any evidence of pathologic change. Although the normal butyl cyanoa’crylate has been shown to be an excellent material for use in the oral cavity, it appears that, on a commercial scale, the production of a variant of this compound called the isobutyl 2-cyanoacrylate will be easier. It is for this reason that the present study was conducted to compare the responses of tissues to the butyl and isobutyl cyanoacrylates. *Chief, Department Dental Research, Walter
of Dental and Oral Pathology, United States Army Reed Army Medical Center, Washington, D. C. 20012.
Institute
of
573
METHODS
AND
MATERI.ALS
This study is based on a histologic analysis of thr tongues of sixty- six rats which were divided into two groups as follows : Group I (experinte~ztal) Thirty-three adult male rats were anesthetized wit,h ether, and t,hei r tongues were extruded and isolated. A midline incision was then m.adt:, extending from the tip to about halfway to the base of the tongue an il
Fig.
Fig.
3
Figs. 1 and 8. Low- and high-power photomicrographs of two halves of rat tong rue which rearponse had been approximated with isobutyl cyanoacrylate 3 days previousty. Inflammatory around adhesive film is minimal. Fig. 2 shows growth of connective tissue “buds” into I ad hesive film.
Volume 26 Number 4
through quickly surfaces 30 days
Oral
surgery-oral
pathology
conference
575
its entire thickness. The two halves of the tongue were then sprayed with a fine mist of isobutyl cyanoacrylate, and the cut were approximated. Animals were killed 0, 3, 5, 10, 14, 21, and postoperatively.
Group II (control)
Thirty-three adult male rats were treated in the same manner as animals of Group I, except that the tongue wounds were approximated with normal butyl cyanoacrylate. After the death of each animal, the tongue was recovered, fixed in formalin, sectioned in the frontal plane at 6 microns, and stained with hematoxylin and eosin. MICROSCOPIC FINDINGS Group I (experimental)
At 0 days the histologic sections revealed a film of the adhesive between the two halves of the tongue which showed no alterations. At 3 days the tissue adjacent to the adhesive revealed areas of minimal edema, as well as plasma-cell and lymphocytic infiltration. In addition, fibroblastic proliferation and growth of fibroblastic buds into the irregularities of the cyanoacrylate spray could be seen (Figs. 1 and 2). Five days postoperatively, the fibroblastic proliferation was more marked, and the cyanoacrylate film was broken up into many fragments by the growth of connective tissue across it (Fig. 3). Histiocytic proliferation and foreignbody giant cells could be seen in the area. Fragments of the adhesive which
Fig. 9. Photomicrograph of B-day specimen (Group I). Fibroblastic proliferation is far advanced, and original film of isobutyl eyanoacrylate is reduced in amount and fragmented.
O.S.,ox & 02.
576 Bhaskar
Fig. 4. Sequestration (arrow) of adhesive healing process; 5day specimen of Group 1.
October, 196s
material
Fig. 5. Photomicrograph of rat tongue 10 days after isobutyl cyanoacrylate (Group I). Note presence of isolated line. These foci are surrounded by histiocytes and giant cells.
which
occurs
approximation cyanoacrylate
simultaneously
with
of incision with foci along incision
were near the surface of the tongue were undergoing sequestration (Fig. 4). In some specimens the cut halves of the tongue had been almost completely repaired with connective tissue and only small amounts of adhesive had remained embedded in the tissues. Ten days postoperatively, fragments of the cyanoacrylate near the tongue surface were being exfoliated and the healing of the incision line by connective
Volume 26 Number 4
Fig. 6. Photomicrograph cytosed particles of adhesive.
Oral
of giant
surgery-oral
cells along
line
pathology
of healed
incision
conference
577
containing
phago-
tissue had progressed further. In the area of the incision, fragments of cyanoacrylate surrounded by histiocytes and giant cells could be seen (Fig. 5). Some of the giant cells appeared to have phagocytosed particles of the chemical adhesive (Fig. 6). In some specimens the tongue surfaces had completely healed and had become epithelized (Fig. 5). Fourteen days postoperatively, the tongue incision had completely healed. Along the incision line, however, isolated foci of histiocytes and giant cells could be seen. It was apparent that the amount of adhesive material in the tongue was far less than was seen at 0 days. This reduction was brought about by sequestration of the adhesive, which was observed in all of the previous stages. It is also possible that the phagocytosis of this material contributed to its disappearance. Twenty-one days after the surgical procedure, the area of the incision showed minimal inflammatory cells or complete absence of such cells. The healed site revealed collagenization, and the adhesive material was seen in small isolated foci in which it was totally surrounded by histiocytes and giant cells. Thirty days postoperatively, healing had progressed further, and the area had become fibrosed. Small foci of cyanoacrylate with surrounding histiocytes and giant cells could still be seen. Group
II (control)
The specimens of Group II showed the same changes as those described in Group I. In both Group I and Group II, isolated specimens were observed which did not fit the general pattern. In these specimens of both early and late stages, the tongue halves had not been approximated promptly or adequately at the time of surgical intervention. For this reason, healing was accompanied by more than normal neutrophilic infiltration and scarring.
578
Bhaskar
OS., ox. & O.P. October, 1968
DISCUSSION
Although most of the experimental work on the effect of chemical adhesives on animal and human oral tissues has been done with the normal but)-1 cyanoacrylate, it appears that the commercial ma,nufacturc of cyanoacrylate adhesives may be limited to the isobutyl cyanoacrylate. For this reason, it appeared necessary to repeat with isobutyl cyanoacrylate some of the original tissue-tolerance experiments that were done with the butpl cyanoacrylate. The present report on the comparison between the normal and isobutyl cyanoacrylate reveals that the two materials are about identical. It would appear, thcrefo,re, at least on the histomorphologic bas’is, that the normal cyanoacrylate can be replaced by the isobutyl cyanoacrylate. In a recent study in which butyl cyanoacrglatc and isobutyl 2-cyanoacrylate were compared wit,h regard to their tissue receptivity on the palatal bone of rats,ll it was shown that t,he isobutyl 2qanoacrylate has a more favorable response than the former. In any event, therefore, it would appear that, both commercially and biologically, the isobutyl 2-cyanoacrylate is at least as acceptable as the butyl cyanoaerylate. SUMMARY
The purpose of the present investigation was to compa,rethe tissue receptivity of the normal butyl and isobutyl cyanoacrylates. The tongues of sixty-six male adult rats were bisected, In thirty-three animals t,he tissue was approximated with isobutyl cyanoacrylate, whereas in the rema,ining thirty-three animals normal butyl cyanoacrylate was used. Specimens were recovered 0 to 30 days postoperatively, cut step-serially at 6 microns, and examined microscopically. Histologic analysis revealed that the tissue response to isobutyl 2-cyanoacrylate is at least as bio-acceptable as that which has been seen with butyl cyanoacrylate. REFERENCES
1. Page, R, C.: Methyl 2Zyanoacrylate Monomer, a Biddegradable Plastic Tissue Adhesive; Review (and supplements), Medical Research Department, Ethicon, Inc., 1966. 2. Bhaskar, 5. N., JacowaT, J. R., Margetis, P. M., Leonard, F., and Pani, K. C.: Oral Tissue Response to Chernlcal Adhesive (Cyanoacrylates), ORAL SURG.,ORAL MED. & ORAL
PATH. 22: 394-404,1966.
3. Bhaskar, S. N., Frisch, J., Margetis, P. M., and Leonard, F.: Response of Rat Tongue to Hextyl, Heptyl and Octyl Cyanoacrylates, ORAL SURG., ORAL MED. & ORAL PATH. 24: 137-144, 1967. on the 4. Bhaskar, S. N., Frisch, J., and Cutright, D. E.: Effect of Butyl Cyanoacrylate Healing of Extraction Wounds, ORAL SURG.,ORAL MED. &ORAL PATH. 24: 604616, 1967. 5. Bhaskar, 5. N., Cutright, D. E., Jacoway J. R., Margetis, P. M., and Leonard, F.: Use of Chemical Adhesives in the Management of Bone Fractures, I.A.D.R. Abst., 47, 1967. 6. Bhaskar, S. N., Frisch, J., Margetis, P, M., and Leonard, F.: Oral Surgery-Oral Pathology Conference No. 18; Application of a New Chemical Adhesive in Periodontics and Oral Surgery, ORAL SURG.,ORALMED.& ORAL PATH.~~: 526-53!$1966. 7. Bhaskar, 5. N., and Frisch, J.: Free Mucosal Graft With Tissue Adhesives, Report of 17 Cases, J. Periodont. 39: 190-195, 1968. 8. Bhaskar, S. N., and Frisch, J.: Use of Cyanoacrylate Adhesives in Dentistry, J. Am. Dent. A. In press. of Skin Wounds Under Butyl Cyano9. Bhaskar, 8. N., and Cutright, D. E.: Healing acrylate Dressing. In preparation, 1968. 10. Bhaskar, S. N.: Unpublished data. Bone to Cyanoacrylate 11. Lobeng R. R., and Sharawy, A. M.: The Response of Alveolar Tissue Adhesives, J. Periodont. 39: X0-156, 1968.
of the
Federal dental services Oral surgery-oral pathology conference
Con,ducted by Surindar N. Bhaskar, Colonel, DC, USA”
B
ecause of their adhesive and hemostatic properties, a family of compounds called the cyanoacrylates has received a great deal of attention. Although the methyl cyanoacrylate is histotoxicl? z and therefore unacceptable for clinical use, it has been shown in this laboratory that a number of other compounds of the cyanoacrylate family are well tolerated by the tissues.2y3 Of the available adhesives, the butyl cyanoacrylate has been the subject of most extensive investigation.4-g This material has been tested in the healing of soft-tissue and bone wounds in animals, and it has also been used as a surface dressing in a variety of surgical procedures on the oral soft tissues of man.2-9 In more than 600 applications in human patients it not only facilitated the healing process but also reduced the operative time, produced immediate hemostasis, and improved the patient’s comfort. 8,lo Biopsy specimens taken from surgical sites 21/2 years after application of this material failed to reveal any evidence of pathologic change. Although the normal butyl cyanoa’crylate has been shown to be an excellent material for use in the oral cavity, it appears that, on a commercial scale, the production of a variant of this compound called the isobutyl 2-cyanoacrylate will be easier. It is for this reason that the present study was conducted to compare the responses of tissues to the butyl and isobutyl cyanoacrylates. *Chief, Department Dental Research, Walter
of Dental and Oral Pathology, United States Army Reed Army Medical Center, Washington, D. C. 20012.
Institute
of
573
METHODS
AND
MATERI.ALS
This study is based on a histologic analysis of thr tongues of sixty- six rats which were divided into two groups as follows : Group I (experinte~ztal) Thirty-three adult male rats were anesthetized wit,h ether, and t,hei r tongues were extruded and isolated. A midline incision was then m.adt:, extending from the tip to about halfway to the base of the tongue an il
Fig.
Fig.
3
Figs. 1 and 8. Low- and high-power photomicrographs of two halves of rat tong rue which rearponse had been approximated with isobutyl cyanoacrylate 3 days previousty. Inflammatory around adhesive film is minimal. Fig. 2 shows growth of connective tissue “buds” into I ad hesive film.
Volume 26 Number 4
through quickly surfaces 30 days
Oral
surgery-oral
pathology
conference
575
its entire thickness. The two halves of the tongue were then sprayed with a fine mist of isobutyl cyanoacrylate, and the cut were approximated. Animals were killed 0, 3, 5, 10, 14, 21, and postoperatively.
Group II (control)
Thirty-three adult male rats were treated in the same manner as animals of Group I, except that the tongue wounds were approximated with normal butyl cyanoacrylate. After the death of each animal, the tongue was recovered, fixed in formalin, sectioned in the frontal plane at 6 microns, and stained with hematoxylin and eosin. MICROSCOPIC FINDINGS Group I (experimental)
At 0 days the histologic sections revealed a film of the adhesive between the two halves of the tongue which showed no alterations. At 3 days the tissue adjacent to the adhesive revealed areas of minimal edema, as well as plasma-cell and lymphocytic infiltration. In addition, fibroblastic proliferation and growth of fibroblastic buds into the irregularities of the cyanoacrylate spray could be seen (Figs. 1 and 2). Five days postoperatively, the fibroblastic proliferation was more marked, and the cyanoacrylate film was broken up into many fragments by the growth of connective tissue across it (Fig. 3). Histiocytic proliferation and foreignbody giant cells could be seen in the area. Fragments of the adhesive which
Fig. 9. Photomicrograph of B-day specimen (Group I). Fibroblastic proliferation is far advanced, and original film of isobutyl eyanoacrylate is reduced in amount and fragmented.
O.S.,ox & 02.
576 Bhaskar
Fig. 4. Sequestration (arrow) of adhesive healing process; 5day specimen of Group 1.
October, 196s
material
Fig. 5. Photomicrograph of rat tongue 10 days after isobutyl cyanoacrylate (Group I). Note presence of isolated line. These foci are surrounded by histiocytes and giant cells.
which
occurs
approximation cyanoacrylate
simultaneously
with
of incision with foci along incision
were near the surface of the tongue were undergoing sequestration (Fig. 4). In some specimens the cut halves of the tongue had been almost completely repaired with connective tissue and only small amounts of adhesive had remained embedded in the tissues. Ten days postoperatively, fragments of the cyanoacrylate near the tongue surface were being exfoliated and the healing of the incision line by connective
Volume 26 Number 4
Fig. 6. Photomicrograph cytosed particles of adhesive.
Oral
of giant
surgery-oral
cells along
line
pathology
of healed
incision
conference
577
containing
phago-
tissue had progressed further. In the area of the incision, fragments of cyanoacrylate surrounded by histiocytes and giant cells could be seen (Fig. 5). Some of the giant cells appeared to have phagocytosed particles of the chemical adhesive (Fig. 6). In some specimens the tongue surfaces had completely healed and had become epithelized (Fig. 5). Fourteen days postoperatively, the tongue incision had completely healed. Along the incision line, however, isolated foci of histiocytes and giant cells could be seen. It was apparent that the amount of adhesive material in the tongue was far less than was seen at 0 days. This reduction was brought about by sequestration of the adhesive, which was observed in all of the previous stages. It is also possible that the phagocytosis of this material contributed to its disappearance. Twenty-one days after the surgical procedure, the area of the incision showed minimal inflammatory cells or complete absence of such cells. The healed site revealed collagenization, and the adhesive material was seen in small isolated foci in which it was totally surrounded by histiocytes and giant cells. Thirty days postoperatively, healing had progressed further, and the area had become fibrosed. Small foci of cyanoacrylate with surrounding histiocytes and giant cells could still be seen. Group
II (control)
The specimens of Group II showed the same changes as those described in Group I. In both Group I and Group II, isolated specimens were observed which did not fit the general pattern. In these specimens of both early and late stages, the tongue halves had not been approximated promptly or adequately at the time of surgical intervention. For this reason, healing was accompanied by more than normal neutrophilic infiltration and scarring.
578
Bhaskar
OS., ox. & O.P. October, 1968
DISCUSSION
Although most of the experimental work on the effect of chemical adhesives on animal and human oral tissues has been done with the normal but)-1 cyanoacrylate, it appears that the commercial ma,nufacturc of cyanoacrylate adhesives may be limited to the isobutyl cyanoacrylate. For this reason, it appeared necessary to repeat with isobutyl cyanoacrylate some of the original tissue-tolerance experiments that were done with the butpl cyanoacrylate. The present report on the comparison between the normal and isobutyl cyanoacrylate reveals that the two materials are about identical. It would appear, thcrefo,re, at least on the histomorphologic bas’is, that the normal cyanoacrylate can be replaced by the isobutyl cyanoacrylate. In a recent study in which butyl cyanoacrglatc and isobutyl 2-cyanoacrylate were compared wit,h regard to their tissue receptivity on the palatal bone of rats,ll it was shown that t,he isobutyl 2qanoacrylate has a more favorable response than the former. In any event, therefore, it would appear that, both commercially and biologically, the isobutyl 2-cyanoacrylate is at least as acceptable as the butyl cyanoaerylate. SUMMARY
The purpose of the present investigation was to compa,rethe tissue receptivity of the normal butyl and isobutyl cyanoacrylates. The tongues of sixty-six male adult rats were bisected, In thirty-three animals t,he tissue was approximated with isobutyl cyanoacrylate, whereas in the rema,ining thirty-three animals normal butyl cyanoacrylate was used. Specimens were recovered 0 to 30 days postoperatively, cut step-serially at 6 microns, and examined microscopically. Histologic analysis revealed that the tissue response to isobutyl 2-cyanoacrylate is at least as bio-acceptable as that which has been seen with butyl cyanoacrylate. REFERENCES
1. Page, R, C.: Methyl 2Zyanoacrylate Monomer, a Biddegradable Plastic Tissue Adhesive; Review (and supplements), Medical Research Department, Ethicon, Inc., 1966. 2. Bhaskar, 5. N., JacowaT, J. R., Margetis, P. M., Leonard, F., and Pani, K. C.: Oral Tissue Response to Chernlcal Adhesive (Cyanoacrylates), ORAL SURG.,ORAL MED. & ORAL
PATH. 22: 394-404,1966.
3. Bhaskar, S. N., Frisch, J., Margetis, P. M., and Leonard, F.: Response of Rat Tongue to Hextyl, Heptyl and Octyl Cyanoacrylates, ORAL SURG., ORAL MED. & ORAL PATH. 24: 137-144, 1967. on the 4. Bhaskar, S. N., Frisch, J., and Cutright, D. E.: Effect of Butyl Cyanoacrylate Healing of Extraction Wounds, ORAL SURG.,ORAL MED. &ORAL PATH. 24: 604616, 1967. 5. Bhaskar, 5. N., Cutright, D. E., Jacoway J. R., Margetis, P. M., and Leonard, F.: Use of Chemical Adhesives in the Management of Bone Fractures, I.A.D.R. Abst., 47, 1967. 6. Bhaskar, S. N., Frisch, J., Margetis, P, M., and Leonard, F.: Oral Surgery-Oral Pathology Conference No. 18; Application of a New Chemical Adhesive in Periodontics and Oral Surgery, ORAL SURG.,ORALMED.& ORAL PATH.~~: 526-53!$1966. 7. Bhaskar, 5. N., and Frisch, J.: Free Mucosal Graft With Tissue Adhesives, Report of 17 Cases, J. Periodont. 39: 190-195, 1968. 8. Bhaskar, S. N., and Frisch, J.: Use of Cyanoacrylate Adhesives in Dentistry, J. Am. Dent. A. In press. of Skin Wounds Under Butyl Cyano9. Bhaskar, 8. N., and Cutright, D. E.: Healing acrylate Dressing. In preparation, 1968. 10. Bhaskar, S. N.: Unpublished data. Bone to Cyanoacrylate 11. Lobeng R. R., and Sharawy, A. M.: The Response of Alveolar Tissue Adhesives, J. Periodont. 39: X0-156, 1968.