THE UN I V E R S I T Y OF M I C H I G A N SCHOOL OF DENTISTRY Department of Oral Surgery Annual Progress Report STUDIES OF FRACTURE HEALING James R. Hayward Gerald H. Bonnette Robert A. Bruce Richard E. Arentz ORA Project 06565 under contract with: U. S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND OFFICE OF THE SURGEON GENERAL WASHINGTON, D.C. CONTRACT NO. DA-49-193-MD-2586 administered through: OFFICE OF RESEARCH ADMINISTRATION ANN ARBOR May 1968

TABLE OF CONTENTS Page LIST OF FIGURES v PART I Introduction 1 Materials and Methods 2 Anesthesia 2 Surgical Procedure 2 Postoperative Management 3 Evaluation Methods 3 Sacrifice Procedure 4 Evaluation Techniques 4 Clinical Impression of Union 4 Radiograph Evaluation 4 Histologic Examination 4 Results 5 Mandibular Fractures 5 Tibial Grafts 5 Stainless Steel Screws 5 Compounded Mandibular Fractures 6 Discussion 6 Summary and Conclusions 7 PART II: A STUDY OF CARILAGE PRODUCTION AND CALLUS FORMATION IN HEALING FRACTURES9 Results 10 References 11 iii

LIST OF FIGURES Figure Page 1. Midline of upper lip six weeks following application of adhesive. 13 2. Midline of upper lip twelve weeks following application of adhesive. 13 3. Saggital section of palate six weeks after application of adhesive. 14 4. Palatal area twelve weeks after application of adhesive, 14 5. Radiographic evidence of nonunion, six weeks after incorporation of adhesive to the fracture site. 15 6. Histologic section of the mandibular fracture six weeks after inclusion of adhesive. 15 7. Subcutaneous abscess associated with mandibular fracture. Intense lymphocytic and polymorphonuclearcytic infiltration was noted. 16 8. Tibia medulla six weeks after injection of adhesive. 16 9. Completed mandibular fracture. 17 10. Application of isobutyl cyanoacrylate adhesive to the Model II mandibular fracture. 17 11. Sutures placed at the completion of the first stage of the Model II operation. 18 12. Placement of a tibia autogenous bone graft to the freshly prepared site at the base of the left mandible. 18 13. Placement of screw holes in the tibia. 19 14. Placement of screws. 19 15. Placement of screws and adhesive. 20 16. Loading the screws with the wire appliance. 20 v

LIST OF FIGURES (Continued) Figure Page 17. Closure. 21 18. Closure. 21 19. Equipment utilized in the spray application of the isobutylcyanoacrylate. 22 20. Spraying of the fracture site. 22 21. Fracture site immediately after spraying. 25 22. Specimen No. 69 immediately after spraying. 23 23. Specimen No. 69 nine days following the spray, 24 24. Specimen No. 70 nine days following compounded fracture without the use of adhesive. 24 25. Specimen No. 69 following debridemrent and closure. 25 26. Specimen No. 69 six weeks later at time of sacrifice, 25 27. Lateral jaw X-ray twelve weeks following body fracture into whnich the cyanoacrylate monomer was incorporated. 26 28, Lateral jaw X-ray six weeks following fracture into which cyanoacrylate monomer was incorporated. 26 29. Lateral jaw X-ray three weeks following fracture into which cyanoacrylate monomer was incorporated. 27 30. Residual isobutyl cyanoacrylate monomer present between the host bone and tibial graft. 27 31, Bony union in a mandible graft. 28 32. Low power (40x) photomicrograph of a compounded fracture sprayed with adhesive. 28 33. Low power(40x) photomicrograph of a compound fracture nonunion. 29 vi

LIST OF FIGURES (Concluded) Figure Page 34. Photomicrograph ( 40x) demonstrating delayed healing in a compound fracture of the mandible. 29 35. Compound fracture of the mandible sprayed with monomer in which treatment was delayed five days. 30 36. Three defects created at the lower border of the monkey mandible. The largest defect is most anterior in position. 30 37. Three trephine defects in the monkey tibia. The largest defeet is most caudal in position. 31 vii

PART I INTRODUCTION (Figs. 1-8) Experimental work with the Macaca Mulatta Rhesus monkey in 1965-19661'2 resulted in the development of a reliable fracture model3 responsive to the influences of altered treatment modalities. After investigation of several healing factors and methods of fixation, we were attracted to the bone adhesive potentials of Isobutyl Cyanoacrylate Monomer, supplied by the Ethicon Corporation. The prototype "Eastman 910 Adhesive" developed in 1960 was methyl-2cyanoacrylate monomer with various additives. The product was purified by the Ethicon Corporation and supplied to several qualified investigators. The methyl form of cyanoacrylate was investigated extensively in animal surgery and in rare human trials. It was applied to small vessel anastomoses, heart and aorta surgery, and in procedures on the lungs, skin, eye, kidney, ureter, bladder, G.I. system, liver, and spleen.5'13 Work on bone and tendon, with one exception,1 was limited to long bones. By 1965, further investigation revealed diminished toxicity achieved by an increase in the length of the alkyl chain.l5,16 The isobutyl form proved to be least irritating to tissues.17 Our pilot studies first involved the use of the material in soft tissue incisions and mucoperiosteal flaps in the rhesus monkeys.2 Healing was satisfactory at 6- and 12-week intervals and showed a minimum of inflammatory response. Our primary interest was the tissue reaction to the acrylate monomer placed in bone. Further pilot studies involved the incorporation of a small amount of the material in the mandibular fracture model of our experimental animals. The adhesive was also used with an autogenous bone graft from tibia to the mandible. Marrow response to the monomer was determined by the injection of a given amount of the material into the medullary portion of the tibia.2 Severe inflammatory response indicated a need for further investigation. In the mandibular fracture, the tissue response included medullary inflammatory reaction to the acrylate 6 weeks following the placement of the adhesive. On the basis of these preliminary observations, a study design included two groups of six monkeys to determine several responses: (1) the effect that Isobutyl Cyanoacrylate Monomer has on the healing of bone in the healing mandibular fracture at 3, 6, and 12 weeks healing intervals. (2) To compare the reaction of a cyanoacrylate on the adherent stable tibial bone 1

grafts. (3) To determine the reaction of bone when the monomer was placed on stainless steel screws set in position, both in stable situations and under conditions of a constant displacing force. (4) To discover what beneficial effects cyanoacrylate may have in the temporary protection of severely compounded fracture injuries and open facial wounds during the period preceding that of definitive treatment. MATERIALS AND METHODS ANESTHESIA Intramuscular phenylcyclidine hydrochloride (Sernylan) was used in all operative procedures. Early problems of inadequate anesthesia or convulsions due to overdosage have been eliminated by a dosage range of 2 milligrams per Kg of body weight. Anesthesia occurs within 10 minutes following intramuscular injection and lasts approximately 2 hours. No endotracheal tube has been necessary; the animal can swallow, cough, and clear any obstruction which might appear. SURGICAL PROCEDURE Mandibular Fracture (Figs. 9-10-11) Approximately 2 weeks following the extraction of the mandibular right second bicuspid or primary second molar and preoperative lateral jaw radiographs, the animal was anesthetized, shaved, and prepared with hexachlorophine soapo The operator scrubbed and gowned, and the animal was draped in the usual sterile manner for the extraoral procedure. The body of the right mandible was exposed by sharp and blunt dissection through a 3 cm incision inferiorly. The cut was made with a No. 6 carbide bur in the region of the previous extraction. The section was continued vertically through medullary bone up to but not including the lingual cortex. Following adequate sectioning, the fracture was completed through the lingual cortex with the twist of an elevator. The fracture was not compounded into the oral cavity. Mobility was demonstrated by manual manipulation. Exactly 2 drops of Isobutyl Cyanoacrylate Monomer was measured from the sterile applicating mechanism supplied by the Ethiccn Corporatio:n and placed in the open fracture site. After adequate hemostasis, the soft tissue was closed in layers and the skin sutured with interrupted 4-0 braided silk sutures. 2

Tibia Bone Grafts (Fig. 12) The anterior surface of the right tibia was exposed in the same 6 animals and a 1 x 1-1/2 x 1/2 cm block of cortical bone was removed. The cortical bone block was returned and stabilized with one drop of the adhesive monomer. Stainless Steel Screws (Figs. 13-18) Two holes, approximately 30 mm apart, were drilled with a Clev-Dent No. 12 bone bur in the left tibia of one animal. Stainless steel screws were placed in these holes. The proximal screw was withdrawn and moistened with one drop of acrylate and immediately replaced. Tissues were closed in layers. The right tibia of two animals was exposed and holes were drilled with their centers exactly 29.5 mm apart. Two screws were set in a similar manner, the adhesive added to the proximal screw and loaded with a previously constructed appliance designed to produce a constant displacing force. Compounded Mandibular Fractures (Figs. 19-26) In the second group of 6 monkeys, a standard mandibular fracture was produced. The reflected soft tissue flap was sutured to expose the bone and simulate a compounded war injury. The animals were divided into three pairs. One of each pair was sprayed with Isobutyl Cyanoacrylate monomer by a method developed by Leonard, et al.l8 The second specimen of the pair served as a control. The animals were returned to their cageso Following a prescribed length of time (2 to 9 days) the animals were reanesthetized and the wounds were thoroughly debrided and closed in layers. The animals were sacrificed following 6 weeks of healing period. POSTOPERATIVE MANAGEMENT After surgery, the animals were placed in their cages with the head hyperextended for recovery from the anesthetic. During the course of healing, all monkeys received a commercial soft diet preparation. Weights were recorded three times in the experimental course. All animals maintained their weight during the healing period observed. EVALUATION METHODS Radiographs Lateral jaw radiographs were exposed: (1) pre-operatively following 15

tooth extraction, (2) postoperatively at the time of fracture, and (3) at the time of sacrifice. Films were exposed 65 kV and 0.4 seconds on Kodak Morlite occlusal dental film. SACRIFICE PROCEDURE After the prescribed healing period, a veterinary lethal solution containing pentobarbital and alcohol vehicle was injected intravenously. The fracture was immediately evaluated for clinical union. The mandible was disarticulated and again a clinical impression for fracture stability was obtained. Following lateral jaw radiography, the specimen was placed in a 10% neutral buffered formalin solution for histological preparation. Histologic Technique The remaining segments were decalcified, dehydrated, infiltrated and embedded in paraffin, serial sections were taken on a horizontal plane, They were mounted and stained alternately with hemotoxyline and eosin, and with masson tri-chrome stain, then covered for histologic study. EVALUATION TECHNIQUES CLINICAL IMPRESSION OF'UNION The firmness of t'he healed fracture was determined immediately after sacrifice by manu;al manipulation. RADIOGRAPH EVALUATION The amount of bony bridge across the fracture site was estimated from lateral jaw radiograph s. HISTOLOGIC EXAMINATION The microscopic sections were evaluated from the standpoint of bony union, fibrous union, or nonunion. The presence of osteoblastic activity and a calcified bond was designated as a bony union. A sectionl showing active osteoblastic proliferation and new bone formation, absence of inflammatory elements in the bone, and the presence of minimal fibrous tissue running perpendicular to the fracture site was classified as fibrous unions 4

A diagnosis of nonunion was made in the absence of osteoid or osteoblastic activity. Osteoclasis and/or inflammation in dense fibrous tissue running parallel to the fracture line was also classed as nonunion. RESULTS MANDIBULAR FRACTURES (Figs, 27-29) All six specimens of this group demonstrated a clinical bony union and a satisfactory healing of the extraoral incision site. Lateral jaw X-rays demonstrated a bony ridge in the 6 and 12 week specimens and a slight bridge in the fracture which was given 3 weeks of healing time. In all histologic sections, bony union was demonstrated in the lingual cortex. There were numerous voids in the medullary and buccal cortex regions previously occupied by adhesive material. Th.ere was fibrosis with a frequent inflammatory cellular response. Osteogenesis was diminished in adjacent areas. The large collection of monomer apparently served to impede the progress of bone formation. The sections of the 5, 6, and 12 week specimens were essentially similar, although the 3 week specimens showed a more acute response, more giant cells, and some eosinophiles. TIBIAL GRAFTS (Figs. 30-31) In a situation not subjected to stress, the results were somewhat different. Histological bony bridging was adequate but still with some isolated voids which represented nondegraded monomero ThYe voids were not as numerous or as severe as observed in the fracture segments (mandibular). STAINLESS STEEL SCREWS The cross section through the hole occupied by the control screw was unimpressive. Cellular response was absent at the end of 3 weeks following the placement of the screws. Areas of bony regeneration were observed. The section of the hole occupied by tie screw upon which adhesive was placed showed cellular response in osne monkey similar to that observed in the mandibular fracture. Giant cells were more numerous here than in any other sections. 5

No clinical difference could be found in the tibia containing the screws placed under constant load, The screw set with adhesive and the control screws appeared the same. Both were firmly anchored 6 weeks following placement, Histologic sections showed little variation between the control screw and the screw placed with adhesive. Small voids were discovered in the latter, but did not appear to significantly alter the histologic pattern. COMPOUNDED MANDIBULAR FRACTURES (Figs. 32-35) Spray application of the adhesive monomer to the compounded fracture site was accompanied by rapid control of bleeding surfaces. The adhesive immediately solidified when contacting the warm, moist bony and soft tissues forming a rather noticeable shield. The period of delay before treatment varied from 2 to 9 days with little variation noted in the six animals. At the time of secondary closure, there was little gross evidence of adhesive. There was no evidence of infection in tbie control or experimental specimens. Healing in all animals proceeded uneventfully and, at the time of sacrifice 6 weeks later, all demonstrated clinical and radiographic union. Histologic union was again demonstrated primarily in the lingual cortex. Bony union was accompanied by formation of cartilage in some specimens. As seen with the preceding six animals, the buccal and medullary areas of bone exposed to the adhesive had voids varying in. size. DISCUSSION Application of the adhesive to the fracture site by the drop method was difficulto Although minimal hemorrhage was controlled, residual bleeding from the medullary areas simply carried tithe adhesive away from the fracture site. Contact with moisture caused immediate coagulation of the monomer; therefore, to successfully use the material in a fracture site, hemorrhage must be controlled and the frature must be held in a reduced position, Under these conditions, the monomer would be drawn i'nto the fracture site by capillary action. In the adhesion of large fragments, the monomer exhibited very little stabilizing effect. The presence of the monomer in the fracture did not appear to influence healing on clinical or radiographic aspects. Histologically, bone healing appeared to require removal of the acrylate monomer and, therefore, the ability of the bone to absorb or exteriorize the monomer to periosteal tissues. Monomer in osseous tissue was characterized by a void surrounded by varying degrees of cellular response from mild fibrosis to acute inflammatory cellular 6

elements including polymorphonuclear leukocytes, eosinophiles, and giant cellso Whether the acute inflammatory response was due to the monomer or was secondary to the surgical procedure cannot be validated, In the case of the small relatively stable fragments, such as the tibia bone graft, the adhesive was found to be of some clinical adhesive value. If requirements of hemostasis and adequate reduction were met, the adhesive was drawn into the fracture line and stabilized the graft in position. Histologic response varied from normal healing to an inflammatory reaction and an excess of monomer may be responsible for this cellular change. During the application of stainless steel screws in the tibia, limited clinical value could be found in the use of the adhesive. Actually, the coagulated adhesive in the screw hole seemed to form a lubricating interface which resulted in less resistance to removal of the screw by the screwdriver. The loaded and unloaded specimens were all retained and were tight at the time of sacrifice. There is some question that the great difference observed histologically in the first unloaded specimen might be due to artifact in the control screw. Very little difference could be noted clinically or histologically in the control and adhesive incorporated screws in the loaded specimens. No tissue or marrow response was seen. A practical spray method was developed to apply thte adhesive to an open wound. The immediate hemostasis observed was dramatic and a significant barrier was indeed present. Unfortunately, our choice of experimental animal in this aspect was poor and we are convinced teat the monkey did not allow the adhesive covering to remain for any length of time. Tte copious blood supply to the area also diminished the possibilities of infection in our control or experimental specimens. In further studies, we would recommend the small of the back of an animal be used where the possibility of interference with the healing of the wound is minimized. Fractures healed better in areas where the adhesive was effectively eliminated as observed in previous specimens. SUMMARY AND CONCLUSIONS 1. Cyanoacrylate monomer did not stabilize large mobile fracture segments. 2. Careful application of a small amount of adhesive seemed to mechanically stabilize small bone grafts. 3. Osteogenesis proceeded effectively as the adhesive was eliminated, but necessitated a delay in repair, 7

4. The monomer produced an inflammatory response that was not predictable or constant. 5. The adhesive did not improve the reaction of bone to stainless steel screws in bony cortex or to their retention. 6. The spray application of adhesive to compounded wounds afforded temporary protection before definitive therapy. Further work is required utilizing better controls for unmolested healing of the wound. 7. Cartilage formation seemed to be related to delayed healing or tissue ischemia. Further study of cartilage forming significance is indicated. 8. An inflammatory cellular response was seen in bone marrow in some animals. This was due to the presence of monomer, tissue contamination or surgical interference. Further investigation is indicated. Whether this reaction was specific for the monomer was not consistently demonstrated and was clouded by other variables. 9. From the studies to date, cyanoacrylate monomer adhesive did not assist in the technical control of fracture fixation. 10. Although not a major deterent to osteogenesis, the adhesive did not enhance the repair process of bone defects studied. 8

PART I I A STUDY OF CARTILAGE PRODUCTION AND CALLUS FORMATION IN HEALING FRACTURES Throughout studies of mandibular fracture repair, cartilage has frequently been observed histologically in the fracture callus of the nonunion animals. Presence of the consistent association of the cartilage with fracture nonunion has stimulated research interest in the relationship between these factors. The literature has described cartilage production to be related to a number of variables such as size of the fracture defect, mobility of the bone fragments, species and age of the experimental animal, anatomical variation, blood supply to the area, oxygen consumption of the tissues, and metabolic requirements. Although the specific cause is uncertain, the presence of cartilage in a repairing fracture site seems to represent a secondary pathway to the eventual production of mature bone. Cartilage which is produced during repair must eventually be replaced by bone through a process of endochrondial ossification thus increasing the L.healing time to bony union, The ultimate goal in treating fractures should be to promote primary bone repair, that is, repair which progresses directly to intramembranous type of bone formation without an initial cartilage phase. Primary osteogenesis may be produced thirough induction substances and extensive study is currently under progress in this area, However, another area for fruitful investigation involves the stimulation of factors responsible for primary osteogenesis and tile elimination of those factors which allow secondary or endochondral ossification to occur. Studies of this type may contribute to clinical methodology which will stimulate fracture healing at an advanced rate. A pilot study was instituted to investigate factors responsible for the presence of cartilage in the fracture site during the repair process. The study was designed to evaluate (1) The relationship of cartilage to the size and position of bone defects. (2) Relationship of mobility to cartilage production. (3) Bone anratomical variatincs and cartilage production, and ( 4) Species and age differe-nces whicl, may- be related to cartilage in the callus o It was deemed necessary to evaluate the bone repair process in the rhesus monkey inr a situatlion l- w-:hich mobility of bo-.e was elimin-ated. This was done by creating three standardized defects at tie inferior border of the mandible through th.e buccal and li.gal cortices inferiorly to the inferior alveolar canalo The cut of 5 mm was placed rear the angle of the 9

mandible and defects of 9 mm and 12 mm were placed in the mid-portion and anterior mandible (Fig. 36). Similar size defects were made in the tibia (Fig, 37) and frontal bone (in a limited number of animals) with the use of trephine burs. This was done to evaluate anatomical differences between bones which developed through either intramembranous or endochondral type formation. In order to test the hypothesis that certain species of animals are so-called "cartilage formers" similar bone defects were made in the mandible and tibia of rabbits under pentobarbital anesthesia. Previous studies had shown that defects of this size would "heal" in approximately 6 weeks in the monkey and 15 days in the rabbit. Therefore, the animals were sacrificed at 3 weeks and 8 days respectively in order to study healing activity at the optimum time. The specimens were decalcified, embedded, cut, and stained with (1) Hematoxylin and Eosin, (2) Toluidine Blue, and (3) a combination of Alcian Blue and Chlorantine Red. These stains were used in an effort to differentiate newly formed cartilage and osteoid. RESULTS The study is still in progress and most specimens are in the decalcification stage, but preliminary results suggest that cartilage production is greatly dependent upon mobility of the bony fragments and disruption of blood supply and is not related to the type of bone, the position or size of the defect, or the species of animal utilized for investigation. Further evaluation is currently underway at the time of h1Lis submission and will be reported in detail in our next quarterly report. 10

REFERENCES 1. Hayward, J,, Bonnette, G., Bruce, R., and Arentz, R., Annual Progress Report, "Studies of Fracture Healing," U.S. Army, April 1966. 2. Hayward, J., Bonnette, G., Bruce, R., and Arentz, R., Annual Progress Report, "Studies of Fracture Healing," U.S. Army, April 1967. 5. Hayward, J., Bonnette, G., Bruce, R., and Arentz, R., "The Development of a Fracture Model," publication pending. 4. Coover, H. W., Jr., Joymer, F. B., Shearer, N. H., Jr,, and Wicher, T. H., Jr., "Chemistry and Performance of Cyanoacrylate Adhesives," Society of Plastic Engineers Journal, 15:5, 1959. 5. Hafner, C. D., Fogarty, T. J., and Stanley, J. J., "Nonsuture Anastomosis of Small Arteries Using a Tissue Adhesive," Surgery, Gynecology and Obstetrics, 116, April 1963. 6. Jacobson, J. H., "The Tissue Response to a Plastic Adhesive Used in Combination with Microsurgical Techniques iin Reconstruction of Small Arteries," Surgery, 60, August 19660 7. Braunward, N. S. and Awe, W. C., "Control of Hemorrhage from the Heart and Aorta Utilizing a Plastic Adhesive," Surgery, 51:6, June 1962, 8. Sawyers, J. J. and Vasko, J., "Sealing Cut Lunag Surfaces with Plastic Adhesive," The Journal of Thoracic and Cardiovascular Surgery, 46:4, October 19635 9. Sussman, M. D., Milch, R. A., Blair, E., Person, E. 0., and Yeager, G. H., "Strength of'Glued? Incisional Wounds," Journal of Surgical Research, 6, 1966. 10. Straatsma, B. R. and Allen, R. A., "Experimental Studies Employing Adhesive Compounds in Opthalmic Surgery," TranrLs American Academy, Opthalmology and Otolaryngology, 67, June 19635 11. Truss, F., Thiel, K. H., and Siemensen, H., "Improved Technique of Nonsuture Closure of Renal Wounds,"' Journal of Urology, 95, May 1966, 12. Strahan, R. W., Sajedee, M., and Duval, M. K., "'The Leaking Esophageal Suture Line-A New Method of Repair Using Eastman 910 Adhesive," American Journal of Surgery, 106, October 1965 11

135. Just-Viera, J. P., Jorge, 0., Aguila, R. P., and Keager, G. H., "Control of Hemorrhage from the Liver Without the Use of Sutures or Clamps: Preliminary Report," The American Surgeon, 28:11, November 1962. 14, Lighterman, E. and Farrell, J. J., "Mandibular Fractures Treated with Plastic Polymers," Archives of Surgery, 87, November 1963. 15. Woodward, S. C., Herrmann, J. B., Cameron, J. L., Brandes, G., Pulaski, R. J., and Leonard, F., "Histotoxicity of Cyanoacrylate Tissues in the Rat, " American Journal of Surgery, 162, 1965. 16. Collins, J. A., Pani, K. C., Lehman, R. A., and Leonard, F., "Biological Substrates and Cure Rates of Cyanoacrylate Tissue Adhesive," Archives of Surgery, 93, September 1966. 17. Bhaskar, S., Frisch, J., Cutright, B., and Margetis, P., "The Effect of Butyl Cyanoacrylate on Healing of Extraction Wounds," Journal of Oral Surgery, Oral Pathology, Oral Medicine, Vol. 24, pages 604:616, November 1967. 18. Leonard, F., Buschey, T., and Cameron, J., "A Spray Gun for a Tissue Adhesive," Surgery, 749-750, May 1965. 12

Figure 1. Midline of upper lip six weeks following application of adhesive. Note minimal foreign body response in muscular layer..................:............ Figure 2. Midline of upper lip twelve weeks following application of adhesive. 13.>~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.........g........ Figure 2. Midline of upper lip twelve weeks follow-~~~~~~~~................. ing applicati on of adhe s ive.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.......... 13~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....

Figure 5. Radiographic evidence of nonunion, six weeks after incorporation of adhesive to the fracture site...... %~~~~~ ~~~~~~~~~~ vl l:::::::::::::;::::::::::::ii.. —....~~~~:,:...."'" "'~~~~ i:':::: i:: I.: i::: ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~S'21o. j~ M ~k wAr ~~~~~~~~~i::::::::*': i~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~:::::::::::::::::::??::::::i~:: ~::,? iii~lr - " ~ "~~~~'~~~'~~......::........... ~"~.'''::..':':':!:::i:"':I::i~-~:'i " i~'~~:.~ I:.:~.~'' M ~ ~ ~ Figure 6. Histologic section of the mandibular fracture six weeks i~'l;lii',ilIj:~.::...._.:~'~:~'~'~i:,i:,l:::t,:.,',::::l:~......:N.' ~:.: ~i'!j!'iii.i:iiii;::ii?''. 4'::'?,,:' ~'::'.:::ll',_i::-...]:i"::I::i~ ~?,~i: i''; i?',',,' ~ ~':~ ~~: -':':i::'~:.:.' i~.- i: i:~:~:::. i::.::~:i~i.ii~:::''l iiiF Fibure g. Histologic section of the mandibular fracture six weeks after inclusion of adhesive. Concentration of adhesive seen at left (buccal cortex). 15

Figure 7. Subcutaneous abscess associated with mandibular fracture. Intense lymphocytic and polymorphonuclearcytic infiltration was noted. Figure 8. Tibia medulla six weeks after injection of adhesive. Reaction to adhesive can be seen on the right.

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Figure 11. Sutures placed at the completion of the first stage of the Model II operation. Figure 12. Placement of a tibia autogenous bone graft to the freshly prepared site at the base of the left mandible. 18

:~: P~`":iF:~W..........~~~~~~~~~~~~~~~~~~~~::..;~~~:''~' ";::::::i~ii~ii:; I:P-, i:. iJ,-:t;"e INS:;; UFA~~~~~~~~~~~~~~~~~~~~~~':: j::i'::~:i:..........~ ~~ ~~ ~ ~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~::~:::.:~:::-::.:..:..............~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~~~;i~iili:;:.:.:: Figure 14. Placement of screws.~~~~~~~~~~~~~:i:

Figure 15. Placement of screws and adhesive. Figure 16. Loading the screws with the wire appliance. 20

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I.,.................................................................................................................. -.-........................................................................................................................................I................................................................................................................................................................................................................... - - - -:::.................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................-......................................................................................................................................................................................................................................................................................................................................... - -.......................................... - -................-.......................................................................................................................................... ------------ ---------------- Figirre.18. Closure,

Figure 19. Equipment utilized in the spray application of the isobutylcyanoacrylate. Figure 20. Spraying of the fracture site. 22

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":~':- ~~- Piz;i 1 *I.~s::._:::'"Xi~ ari,~ i::: Figure 22. Specimen No. g immediately after spraying.

Figure 23. Specimen No. 69 nine days following the spray. ~ii~ii:-i~i~i~::::2:ir:::::i!::.i:;{:i:L::i::::::::::::::i:::::::::i::: - iii~~~~~~~~~~~~~~~~~~~~~~~~~~ii~~~~~~~~~~~~~~~~~~~ii~~~~~~~~~~~~~~~~~~~~i:'iii~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ii ~ ~ ~ ~ ~ ~: ii:): wihot h use ofdheive ~::? g.~.EE -,.:? E ~.v:'' #:':.: i:::::::::: 1:?:::::,::, iE::::::::::::::.?.t>:<.:?.:?E:E:::EV::<:: i::::E:?E:?:E::::.:E:E::::: E~~~iE:ERE::::E::::::?::::::::':::::?::::::::::::::-:i s:E:-:::i::::.::::i:::,::::::::~::::::::::'::Eis:l:::::s::.E:Bs.:l-:':::.?E:::Es':::Ej:::E:E:E::i:::::E E:::: E::E::E::.:::E:::::::::::::::E::::::::'i"''i lil'ii~~i: g::::iZ::::E: g:::.S.:.::.s:':.::::.:.~-.:R?'SEE::E.::::-.:.:::::E::::iE i?:,#:::::::::: - ~::::::; g:i:.:::,'"::~~::: i: i:::: i: -:::s:,~b, > ~-:?-::::.::i~~i':::':i:'i.::',":::':::,':'::::::?:_ii~eii;~ii~i':i:i:::::.::. Rg:R::;?::: s: i# -:::??2::: E::;::: 0 il:::: l R:'::::i:: I:i:: X::::g;l,:::t: iBB;:,g.:: i:: 5.:: i': 0E:::;g,::::?::::,:: gf.:::g!z g g;:l ~~::;, a?,Ri.:-. g g::,Z =::s i:::i::ii-:;i::;SS:ii~~::-8jR, i;~::i::l~l?g:.:;g.:::;i:.::i:::,i:::: s!'...:::,l::::Rii': -: >::I:::si::i:i: 0.::'i'_,'i ~..~.....::;: j: ii b, i:~~~~~~~~~~~~~~~~~ ~~~~~::::.:::.'::~..:.:..::: f:-;;::-:::;-': iEE gs. ~~~~~~~~~~~~~'0;;'?...: "::i:2-i;i:?i':0:':;:;:0~ 0:::;;:0:;;::E:-:::0:i"' E;i:"'| i:: ~ - - >: -::i: -- X a i I __ I::I:::::'':'::::::::::::::::::..::i~~~~~~.::.;':::/:iiiiiiiii li ii~. L.'.:~;~~':::~~:i:~i::~'~~:::~i:::~:,iii Figure 24. Specimen No. 70.nine days following compounded fracture without the use of adhe sive. 24

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Figure 27. Lateral jaw X-ray twelve weeks following body fracture into which the cyanoacrylate monomer was incorporated. Figure 28. Lateral jaw X-ray six weeks following fracture into which cyanoacrylate monomer was incorporated. 26

Figure 29. Lateral jaw X-ray three weeks following fracture into which cyanoacrylate monomer was incorporated. Figure 30. Residual isobutyl cyanoacrylate monomer present between the host bone and tibial graft. Note the minimal inflammatory response which was characteristic in the bone grafting procedures. 27

Figure 31. Bony union in a mandible graft. Fibrous connective tissue is noted in the center of the photomicrograph with areas of monomer and debris. Figure 32. Low power (40x) photomicrograph of a compounded fracture sprayed with adhesive. Note the intense cartilage formation between the fracture sites. 28

Figure 33. Low power (40x) photomicrograph of a compound fracture nonunion. Note the fibrocellular response on the buccal surface with areas of residual monomer. Figure 34. Photomicrograph (40x) demonstrating delayed healing in a compound fracture of the mandible. Note the dense fibrous connective tissue in the center of the section with ostenogenesis occurring on the left, 29

Figure 35. Compound fracture of the mandible sprayed with monomer in which treatment was delayed five days. Note the presence of monomer at the lower border of the photomicrograph. Figure 36. Three defects created at the lower border of the monkey mandible. The largest defect is most anterior in position. 50

: /:..:.:.::::::::::ic::i:-::::i:::.....-::I:~:::::::::::: i:::::ii:i:i::i:::i::::: I:::.::i::i:i:::( ii::::.::..:::iiii:iii:::::: i:::::::::::...:-:::::::::::::::i:::::::::::::::::::.....::Si':ii"i"i':l:i::::il:::::::i:::l:i::::::::(:::::i -:' j::n::::::,,,,,,:i:i:~i:saP~aa~lla~i~~~:"::j:,,:i:;:;i:il:i~:::::::::::::ii::iiiiii ":":2:::::iii:::::::::.:-:: i: iiiii:i:iiii:i: I:lii"iil:iii::::::::i:iii'ii:iii:i:iii:..::_::::;:::::::iiiii:i:ii::i:::lili::l:i::::::::-,:i: -li::i:~::i:;:i:i:ic~::~l:::::;:i:li:.:::::_::i:::::l,.':'::::::::: E'siii-ii-ii)iii:':iiiiiis::ii':::::j::-~~::::j:::- ~~ — i:::::::- iiiii!i'''''':::::l'::'''::':::~'~'::::i:::::aiii:::i::::~:::i:i:::-:i::::.::':::: ,ikl::::ii:i::::: I:i:::`:::::::i:-:;: E%' a:-I 1,~ c~r-~~ i:::-::::i:: $lii iiiei:::::ii:.:....:.....: ii:::::::::: iai;-iiiii::':::: i: i:i i:::...:.::::: iil iiiiiiiiii:i:i:;i:::i:::::::::....:...: ni:-::8:i-:il:::::ic::: -...-::::':'~i::i:::'-:i:::::::-:::::': iiii:iii:i:i::::::::::: li;,i~;:ri:::.::::::: -''' I:iiii::::::li::-:::i:::i:i: Fiure 37. Three trephine defects in the monkey tibia. The largest defect is most caudal in position. 31

Unclassified Security Classification DOCUMENT CONTROL DATA - R&D (Security claaallcation of title, body of abstract and indexing annotation must be entered when the overall report is classified) 1. ORIGINATING ACTIVITY (Corporate author) 2a. REPORT SECURITY C LASSIFICATION The University of Michigan Unclassified School of Dentistry, Department of Oral Surgery 2b GROUP Ann Arbor, Michigan 3. REPORT TITLE STUDIES OF FRACTURE HEALING 4. DESCRIPTIVE NOTES (Type of report and inclusive date.) Annual Progress Report 5. AUTHOR(S) (Last name. tirtt name, initial) Hayward, James R., Bonnette, Gerald H., Bruce, Robert A., Arentz, Richard E. 6. REIPORT DATE 7a. TOTAL NO. OF PAGE 7. NO. OF REPS May 1968 31 18 8-. CONTRACT OR GRANT NO. 9a. ORIGINATOR'S REPORT NUMBER(S) DA-49-193-MD-2586 o6565-5-P b. PROJECT NO. c. 9 6. OTHER REPORT NO(S) (Any other numbera that may be assagned Cis. riport) d. 10. A V A IL ABILITY/LIMITAtION NOTICES Qualified requesters may obtain copies of this report from DDC 11. SUPPLEMENTARY NOTES 12. SPONSORING MILITARY ACTIVITY U. S. Army Medical R and D Command Office of the Surgeon General Washington, D.C. 13. ABSTRACT Investigations were designed to determine the effects of Isobutyl Cyanoacrylate Monomer on: (1) healing mandibular fractures, (2) tibial bone grafts, (3) the stability of stainless steel bone screws, and (4) severely compounded fractures and facial injuries. The experimental animalsiused were the Macaca Mulatta Rhesus monkeys, and the results obtained were evaluated by clinical, radiographic, and histologic methods. Results demonstrated that adhesive would stabilize small bone grafts but not mobile fractures. The cyanoacrylate monomer tended to retard osteogenesis and did not aid in the retention of bone screws under tension. Application of the monomer to compounded wounds aided in hemostasis and offered temporary protection to the wound. Further studies were designed to evaluate the functional role of fibrocartilage in the healing callus. Preliminary results indicate that cartilage production is dependent upon bone mobility and disruption of adjacent blood supply and periosteum and is not related to the type of bone, position or size of the defect, or species of animal. D D *JAN64 1473 Unclassified Security Classification

Unclassified Security Classification ~~14~. KEY WORDS LINK A LINK B LINK C KEY WORDS ROLE WT ROLE WT ROLE WT Mandible Fracture Rhesus monkeys Isobutyl cyanoacrylate monomer LDH activity Aerobic Anaerobic INSTRUCTIONS 1. ORIGINATING ACTIVITY: Enter the name and address imposed by security classification, using standard statements of the contractor, subcontractor, grantee, Department of De- such as: fense activity or other organization (corporate author) issuing (1) "Qualified requesters may obtain copies of this the report. ( I report from DDC." 2a. REPORT SECURITY CLASSIFICATION: Enter the over2a. REPORT SECUTY CLASSIFICATION: Enter the, over- (2) "Foreign announcement and dissemination of this all security classification of the report. Indicate whether "Restricted Data" is included Marking is to be in accord- report by DDC s not authorze ance with appropriate security regulations. (3) "U. S. Government agencies may obtain copies of this report directly from DDC. Other qualified DDC 2b. GROUP: Automatic downgrading is specified in DoD Di-uses shll t th rective 5200. 10 and Armed Forces Industrial Manual. Enter the group number. Also, when applicable, show that optional. markings have been used for Group 3 and Group 4 as author- (4) U. S. military agencies may obtain copies of this ~~~~~~~~ize~~~d~. ~report directly from DDC. Other qualified users 3. REPORT TITLE: Enter the complete report title in all shall request through capital letters. Titles in all cases should be unclassified.,, If a meaningful title cannot be selected without classification, show title classification in all capitals in parenthesis (5) "All distribution of this report is controlled. Qualimmediately following the title. ified DDC users shall request through 4. DESCRIPTIVE NOTES: IT appropriate, enter the type of. _____ report, e.g., interim, progress, summary, annual, or final. If the report has been furnished to the Office of Technical Give the inclusive dates when a specific reporting period is Services, Department of Commerce, for sale to the public, indicovered. cate this fact and enter the price, if known. 5. AUTHOR(S): Enter the name(s) of author(s) as shown on 11. SUPPLEMENTARY NOTES: Use for additional explanaor in the report. Enter last name, first name, middle initial, tory notes. If military, show rank and branch of service. The name of the principal author is an absolute minimum requirement. 12. SPONSORING MILITARY ACTIVITY: Enter the name of the departmental project office or laboratory sponsoring (pay6. REPORT DATE: Enter the date of the report as day, ing for) the research and development. Include address. month, year; or month, year. If more than one date appears on the report, use date of publication, 13. ABSTRACT: Enter an abstract giving a brief and factual summary of the document indicative of the report, even though 7a. TOTAL NUMBER OF PAGES: The total page count it may also appear elsewhere in the body of the technical reshould follow normal pagination procedures, i.e., enter the port. If additional space is required, a continuation sheet shall number of pages containing information be attached. 76. NUMBER OF REFERENCES: Enter the total number of It is highly desirable that the abstract of classified reports references cited in the report. be unclassified. Each paragraph of the abstract shall end with 8a. CONTRACT OR GRANT NUMBER: If appropriate, enter an indication of the military security classification of the inthe applicable number of the contract or grant under which formation in the paragraph, represented as (TS), (S). (C). or (U) the report was written IThere is no limitation on the length of the abstract. How8b, 8c, & 8d. PROJECT NUMBER: Enter the appropriate ever, the suggested length is from 150 to 225 words. military department identification, such as project number, 4. K W K word ar n nn r subproject n umber,,, system numbers,- task,, number et,. 14 KEY WORDS: Key words are technically meaningful terms or short phrases that characterize a report and may be used as 9a. ORIGINATOR'S REPORT NUMBER(S): Enter the offi- index entries for cataloging the report. Key words must be cial report number by which the document will be identified selected so that no security classification is required. Identiand controlled by the originating activity. This number must fiers, such as equipment model designation, trade name, military be unique to this report. project code name, geographic location, may be used as key 96. OTHER REPORT NUMBER(S): If the report has been words but will be followed by an indication of technical conassigned any other report numbers (either by the originator The assignment of links, rules, and weights is optional or by the sponsor), also enter this number(s). 10. AVAILABILITY/LIMITATION NOTICES: Enter any limitations on further dissemination of the report, other than those Unclassified Security Classification

UNIVERSITY OF MICHIGAN 3 9015 03026 6731