GLOBUS MEDICAL, INC.
`EXHIBIT 1018
`IPR2015-to be assigned
`(Globus v. Flexuspine)
`
`1 of 6
`
`

`
`8
`
`VETERINARY SURGERY
`
`January-March 1979
`
`Vol. 8
`
`TABLE 1. Degree of Clinical Proprioceptive Gait
`Deficit (After Mayhew”)
`
`Grade
`
`Description
`
`0
`1
`
`2
`
`3
`
`4
`
`Deficit not detected.
`Deficit detected at normal gait or posture but min-
`imal in degree.
`Deficit easily detected and exaggerated by back-
`ing and turning.
`Deficit very prominent at normal gait with a
`tendency to buckle or fall with backing and turn-
`mg.
`Stumbling, tripping, and falling spontaneously at
`normal gait.
`
`and the source of the graft material.” In essence, how-
`ever. the technique remains the same and anterior fu-
`sion is widely accepted as a means of stabilizing the
`human cervical spine. Satisfactory results have been
`reported in 80-90% of all cases.7»‘°"3
`This paper describes a ventral approach to the
`equine cervical spine and interbody vertebral fusion
`utilizing homologous bone from equine ilia.
`
`Materials and Methods
`
`Harvesting Bone Dowels
`
`Autogenous bone was difficult to obtain as dorsal position-
`ing of the horse for ventral cervical surgery made the ap-
`
`proach to the ilium awkward. Therefore, an equine cadaver
`bone bank was established to decrease operative time and to
`avoid the necessity of a second incision in the same patient.
`Bone dowels were obtained and stored in a manner similar to
`that described for human beings.2“3
`Bone dowels were harvested from cadavers of horses that
`had been destroyed for reasons other than systemic disease.
`The skin over the ilia of fresh cadavers was prepared by
`scrubbing with an iodine preparation* followed by alcohol
`rinse. The operative site was draped and an incision was
`made over the dorsal edge of the ilium. Muscle and perios-
`teum were removed from the wing of the ilium. An 18-mm
`dowel cutterl was used to remove 8-10 full-thickness dow-
`els from each ilium. The dowels varied in length from 30 to
`50 mm depending on the thickness of the ilia and consisted of
`largely canccllous bone with plates of cortical bone at each
`end. The bone dowels were soaked in a solution of 500 ml of
`sterile saline solution containing 1 g of Neomycin, 5,000,000
`U of Polymixin B and 5,000,000 U of Lincomycin for 30
`minutes. Dowels were then packaged separately in sterile
`plastic bags and frozen at -70°C until used. The bone grafts '
`were thawed for at least 1 hour prior to implantation.
`
`Preoperative Preparation
`
`Twelve horses ranging in age from 3 months to 2 years
`were selected for use in the investigation. All horses under-
`went complete physical and neurologic examinations. Prior
`to surgery, the proprioceptive gait deficits in each horse were
`evaluated on a scale from 0 to 4 (Table 1). Nine of the horses
`had been diagnosed as having cervical vertebral malforma-
`tion on the basis of clinical and radiographic findings. Three
`healthy horses were selected as controls.
`Twenty-four hours prior to surgery, a prophylactic treat-
`ment regimen of procaine penicillin G (30,000 U/kg) and di-
`hydrostreptornycin (7 g/day) was begun. The entire neck
`from the head to the shoulder was clipped and the ventral
`midline was shaved and washed with a dilute iodine prepara-
`tion.
`
`Operative Technique
`
`The patient was anesthetized and positioned in dorsal re-
`cumbency with the neck extended. The depth of the verte-
`bral body had been preoperatively estimated from a lateral
`radiograph. A radiographic cassette positioned lateral to the
`cervical area determined the level of the venebral fusion
`intraoperatively. After final preoperative preparation with
`iodine scrub and alcohol. the ventral aspect of the neck was
`covered with a large self-adherent plastic draped: The inci-
`sion site was surrounded with surgical drapes.
`A 30-cm skin incision was made on the ventral mid-line
`beginning 20 cm posterior to the wing of the atlas. The deep
`incision was continued between the bellies of the ster-
`nothyrohyoideus muscles, which were then retracted. The
`deep cervical fascia between the trachea and the carotid
`sheath was divided longitudinally using blunt dissection. The
`trachea was retracted to the left, and the right external jugu-
`lar vein, carotid artery, and vagus nerve were retracted to
`
`
`* Weladol Therapeutic Shampoo, Pittman-Moore,
`Washington Crossing, New Jersey 08560.
`T Zimmer. U.S.A., Warsaw, Indiana 46580.
`if Vi-Drape, Parke-Davis & Company, Detroit, Michigan 48232.
`
`Inc.,
`
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`
`Ventral Crest
`
`Longus Colli Muscle
`
`Sternothyrohyoideus M.
`Bi Carotid Sheath
`
`Trachea
`
`Sternothyrohyoideus M.
`
`Fig. 1. The operative approach to the equine ventral spine.
`
`

`
`No.
`
`1
`
`EQUINE CERVICAL SPINE
`
`-
`
`Wagner, et al
`
`9 F
`
`the right (Fig. I), thus allowing palpation of the ventral crest
`through the longus colli muscles. A Steinman pin was placed
`in the ventral crest at the level to be fused, and a lateral
`radiograph served to confirm that the marker pin was at the
`correct space (Fig. 2).
`The longus colli muscles were retracted following separa-
`tion from the bone by a periosteal elevator. The ventral crest
`was exposed and removed with rongeurs to prepare a level
`bed for the drill guide.
`Special instruments for drilling the hole across the disc
`space included a Cloward twist drill (16 mm), a pronged
`guard, and 21 Hudson cranial drill brace§ (Fig. 3). The guard
`was centered over the intervertebral space and secured in
`the bone by gentle tapping with a mallet. An assistant braced
`the guard while the surgeon drilled out the bone and interver-
`tebral disc. The drill and guide were removed periodically to
`evacuate debris and evaluate positioning. Positioning was
`considered correct if the disc appeared near the center of the
`hole (Fig. 4). The equine disc space curves cranially. neces-
`sitating slight rcdirection of the drill as the hole was drilled.
`The white, fibrous disc material was easily identified. Debris
`was removed periodically with a sharp curette and pituitary
`rongeurs. At a depth of approximately 15 mm, the guard was
`removed and the drilling continued “freehand.” Estimation
`of proximity to the spinal canal was based on periodic meas-
`urement with a depth gauge during the drilling process. Care
`was taken to avoid perforation of the vertebral body cortex
`and the underlying dorsal ligament and spinal cord. Drilling
`was complete when only a thin wall of cortical bone re-
`mained between the drill and the dorsal ligament. This thin
`wall was removed with a spinal curette, and the hole was
`cleared of debris and flared at its dorsal edge.
`The thawed bone dowel was placed on a Cloward dowel
`impactor handle" (Fig. 5). smoothed with a bone rasp, and
`adjusted to fit the depth of the hole. The bone dowel was
`inserted into the site and tamped so that it was even with or
`just below the edge of the hole. The longus colli muscles and
`the bellies of the sternothyrohyoideus muscles were apposed
`using simple interrupted sutures. The subcutaneous tissue
`and skin incision were closed with interrupted mattress su-
`tures.
`
`the
`Following the animal’s recovery from anesthesia,
`wound was covered with a sterile towel and elastic tape to
`avoid contamination. Feed and water were elevated to dis-
`courage excessive flexion of the neck. Antibiotics were ad-
`ministered for 5 days postoperatively. Bandages and sutures
`were removed 14 days postoperatively. After 1 month of
`confinement to a stall, the horse was permitted access to a
`large paddock.
`
`Results
`
`Immediate Postoperative Results
`
`All 12 horses recovered uneventfully and were
`standing within 1 hour following extubation. Two ani-
`mals had to be assisted in arising; however, both had
`been severely ataxic preoperatively.
`Postoperative stiffness in the cervical area and vent-
`ral swelling were exhibited by all horses and persisted
`
`
`§ Codman and Shurtleff, Randolph, Massachusetts 02368.
`" Codman and Shurtleff, Randolph. Massachusetts 02368.
`
`ig. 2. Radiograph obtained after approximate cervical
`level was reached. Pins are inserted into the disc space to ascer-
`tain correctness of the approach.
`
`for 7 days. Anti-inflammatory or analgesic drugs were
`not administered. A cervical neck brace was designed
`for the first horse; however.
`this was discarded be-
`cause of its unwieldly nature. The swelling and stiff-
`ness seemed to sufficiently deter motion in the cervical
`area.
`
`Preoperatively, clinical signs of the horses with
`CVM were rated on a scale of 0-4, after the classifica-
`tion of Mayhewf‘ There was clinical improvement of at
`least I grade in all affected horses 3-6 months post-
`operatively. The 3 normal horses showed no adverse
`central nervous system signs.
`Horses 4 and 6 showed gluteal myositis immediately
`following surgery. This was attributed to intraopera-
`tive positioning. Horse 6 recovered completely, but
`horse 4 showed slight gluteal atrophy throughout the
`study.
`
`
`
`Fig. 3.
`Instruments used in producing the opening to the
`spinal canal. from left to right include: a Hudson cranial drill
`brace, a twist drill, and a drill guard with adjustable screw and
`lock.
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`10
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`VETERINARY SURGERY
`
`January-March 1979
`
`VOL 3
`
`
`
`Fig. 4. Drilling of the opening between the vertebrae.
`Positioning is checked periodically to assure that the appear-
`ance of the disc in the center of the hole is as shown in the inset.
`
`All incisions healed by first intention. A hematoma
`appeared laterally to the incision in 1 horse but was
`resolved within several days.
`Postmortem examinations were performed on 9
`horses 3 months postoperatively and on 3 horses 6
`months postoperatively.
`
`Radiographic Results
`
`The operative sites were examined radiographically
`in all horses prior to euthanasia. Xeroradiographs were
`
`
`
`Fig. 5. The bone plug is fitted to the Cloward dowel impac-
`tor handle and placed in the hole. The fit is tight since the dowel
`is 1-2 mm larger than the hole.
`
`
`
`Fig. 6. Radiograph appearance of the operative site 3
`months postoperatively (arrow).
`
`made of the dissected cervical spinal column following
`the post mortem examination.
`Radiographic examination of 11 sites in 9 horses 3
`months postoperatively indicated 5 complete ar-
`throdeses, S fibrous fusions, and I nonunion. The re-
`sults of radiographic examination of 3 horses 6 months
`postoperatively were:
`1 nonfusion,
`1 fibrous fusion,
`and l arthrodesis. The radiographic appearance of
`complete fusion is illustrated in Fig. 6. The normal
`controls did not differ from the CVM horses. Radio-
`
`graphic interpretations are correlated with clinical im-
`provement in Table 2.
`Xeroradiographic examination substantiated these
`findings and assisted in the demonstration of the
`trabecular reorganization at the vertebral end plates.
`
`Gross Pathologic Results
`
`At necropsy, the spinal column was cut longitudi-
`nally as close to the midline as possible without damag-
`ing the cord. The appearance of complete fusion at
`C3_4 is shown in Fig. 7. Immobility created at the
`operative site was evaluated subjectively by the
`amount of movement during flexion and objectively by
`measuring the decrease in the diameter of the canal
`when the neck was flexed. The amount of movement
`
`im-
`
`the operative site is correlated with clinical
`at
`provement in Table 2.
`In the 9 horses evaluated 3 months postoperatively,
`2 surgical sites had not fused. 7 exhibited a strong
`fibrous fusion, and 2 had bony union. The average
`decrease in spinal canal diameter when the neck was
`flexed was 2.5 mm for the unfused, 0.8 mm for the
`fibrous fusion, and 0 mm for the bony fusions.
`Necropsy of the horses 6 months postoperatively
`demonstrated 1 nonunion and 2 fibrous fusions. The
`decrease in spinal canal diameter when the neck was
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`No.
`
`1
`
`EQUINE CERVICAL SPINE
`
`'
`
`Wagner, et al
`
`11
`
`TABLE 2. Results of Cervical Stabilization at 3 and 6 Months Postoperatively
`Decrease in Canal
`Diameter at Operative
`Site on Flexion (mm)
`
`Horse
`
`Breed
`
`Age
`
`Sex
`
`Operative Preoperative Postoperative
`Level
`Grade
`Grade
`
`Fladiographic
`Diagnosis
`
`Controls—3 months
`1 Quarter Horse
`2
`POA
`3 Quarter Horse
`Patients—3 months
`4 Thoroughbred
`5 Thoroughbred
`6 American Saddle
`7 Quarter Horse
`8 American Saddle
`9 Quarter Horse
`Patients—6 months
`
`6 mo M/C C3-..
`6 mo M/C CH
`2 yr
`M/C CH
`
`M/C CH. CH
`1.5 yr
`F
`C3 .4
`2 yr
`F
`C2-3, C3...
`3 mo
`F
`C3_4
`2 yr
`3 mo M/C CH
`3 yr
`F
`CH
`
`0
`0
`0
`
`2.5
`2
`3.5
`3
`3
`2.5
`
`10 Quarter Horse
`11
`Thoroughbred Cross
`12 Thoroughtbred
`
`6 mo
`15 mo
`2 yr
`
`03...
`M
`C3-..
`F
`M/C CH
`
`3.5
`3
`3
`
`/C = Castrated male
`POA = Pony of the Americas
`
`0 M
`
`O
`0
`0
`
`1
`0
`2
`2
`1.5
`2
`
`1.5
`
`1.5
`
`Fused
`Fused
`Partial
`
`Not fused. partial
`Fused
`Fused, partial
`Partial
`Partial
`Fused
`
`0
`0
`1
`
`Not clone
`2
`0,2
`3
`1
`0
`
`Partial
`Not fused
`Fused
`
`0
`1
`
`flexed was 3 mm in the case of the nonunion, and 0 mm
`in the fibrous unions.
`
`The results of histopathologic examination of the
`spinal cord and the operative fusion site will be the
`substance of another report.“
`
`Discussion
`
`Fusion of the cervical vertebrae in humans by an
`anterior approach has been practiced since 1958.9 This
`has also been successfully used in dogs,“"2-“"*2"’ and
`has met with acceptance in the treatment of canine
`caudal cervical malarticulation malformations because
`of the ease of exposure and minimal tissue damage
`incurred.
`The bone dowels inserted in the drilled out disc
`
`space act as a scaffold for the host osteogenic tissue.”
`Invasion and revascularization by host cells as early as
`3 days after placement of grafts has been reported.“
`Graft rejections have not constituted a clinical problem
`and recent studies have indicated that freezing may
`actually decreae host antigenic response.” The use of
`bone dowels obtained from equine cadavers markedly
`reduced the operative time.
`The operative approach to the ventral aspect of the
`equine cervical spine is not difficult, although some
`vital structures must be avoided. The carotid artery,
`vagus nerve, and recurrent laryngeal nerve must be
`retracted for extended periods, and in one case, there
`was permanent right laryngeal hemiplegia postopera-
`tively. This may have been due to intraoperative nerve
`damage.
`
`Evacuation of cervical disc material is difficult in the
`
`horse because the disc space is strongly curved, and
`the disc material consists of heavy fibrous tissue with
`fibrocartilage firmly attached to the adjacent verte-
`brae. Although not encountered in this study, possible
`complications include hemorrhage from the ventral
`venous sinuses as described in dogs,” respiratory
`nerve damage.” and mechanical failure of the dowel?”
`
`Radiographic appearance of arthrodesis and the re-
`lief of clinical symptoms have been used as criteria for
`the quality of intervertebral fusion in humans.”-'0 Fu-
`sion was apparent radiographically at 6-8 weeks post-
`operatively. These patients were not examined after
`death to determine whether radiographic fusion re-
`tlected true osseous fusion. In this study, the radio-
`
`
`
`Fig. 7. The postmortem appearance of fusion at the surgical
`site 3 months after surgery (arrow).
`
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`12
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`VETERINARY SURGERY
`
`January—March 1979
`
`Vol. 8
`
`graphic diagnosis of complete versus early fusions
`could not be clearly differentiated.
`This study has established that operative arthrodesis
`is possible in the horse. Fusion might be more readily
`achieved if the instruments were larger, allowing
`placement of a 20—mm bone dowel. This would allow
`operative removal of a larger area of disc material
`which appears to interfere with fusion.
`The technique offers an alternative to ventral plating
`of the spine, wiring of the articular facets, and dorsal
`spinal grafting procedures for stabilization of the cer-
`vical spine. Possible applications other than the use in
`cervical vertebral malformation might include fixation
`of traumatic cervical fractures and cervical instability
`due to osteolytic processes.
`
`References
`
`1. Beech J: Cervical cord compression and wobbles in horses.
`Proc Am Assoc Equine Pract 22: 79, 1976.
`2. Fraser H, Palmer AC: Equine incoordination and Wobbler dis-
`ease in young horses. Vet Rec 80: 338, 1976.
`3. Mayhew IG, deLahunta A, Whitlock RH, et al: Spinal cord
`diseases in the horse. Cornell Vet 68 Suppl 6, 1978.
`4. Prickett ME: Equine spinal ataxia. Proc Am Assoc Equine Pract
`14: 147, 1968.
`5. Rooney JR: Equine incoordination 1. Gross morphology, Cor-
`nell Vet 53: 411, 1963.
`6. Steel ID, Whitten JH, Hutchins DR: Equine sensory ataxia
`“wobbles." Aust Vet J 35: 442, 1959.
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`the cervical spine. Surg Clin North Am 41: 1661, 1961.
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`tion in a dog. J Am Vet Med Assoc 160: 424, 1972.
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`cervical discs. J Neurosurg 5: 602, 1958.
`10. Dohn DF: Anterior interbody fusion for treatment of cervical-
`disc conditions. JAMA 197: 175, 1966.
`ll. Popovic NA, VanderArk G, Kempe L: Ventral approach for
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`Vet Res 32: 1155, 1971.
`12. Prata RG, Stoll SG: Ventral decompression and fusion for the
`
`treatment of cervical disc disease in the dog. J Am Amm
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`I3. Simmons EH, Bhalla SK: Anterior cervical discectomy and fu-
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`15. Trotter EJ, deLahunta A, Geary JC, et al: Caudal cervical ver-
`tebral malformation malarticulation in Great Danes and
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`the cervical spine. Clin Orthop 109: 78, 1975.
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`served bone allografts. Transplant Proc Suppl 1: 73, 1976.
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`22. Brown MD, Malinin TI, Davis PB: A roentgenographic evalua-
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`lar bone grafts. Ital J Orthop Traumatol 2: 151, 1976.
`27. Lozano AJ, Cestero HJ, Salyer KE: The early vascularization
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`28. Langer F, Czitrom A, Pritzker KP, et at: The immunogenicity of
`fresh and frozen allogenic bone. J Bone Joint Surg 57-A: 216,
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`
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