GLOBUS MEDICAL, INC.
`EXHIBIT 1015
`IPR2015-to be assigned
`(Globus v. Bonutti)
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`180
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`CAMERON, MACNAB, AND PILLIAR
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`MATERIALS AND METHODS
`
`(trade name Synthos; Miter Inc., Worthington,
`This material
`Ohio) is produced from calcium phosphate powder by isostatic press-
`ing; it is then sintered to produce a single—phase B-tricalcium phos-
`phate. The powder is mixed with naphthalene, which evaporates
`during the process, leaving pores within the ceramic. There is a
`uniform distribution of large,
`interconnecting pores ranging from
`100 to 300 p in size. The material, as available, has a 36% porosity.
`Experiments were divided into two phases: toxicity testing and
`bone ingrowth evaluation.
`
`TOXICITY TESTING
`
`the material,
`Twelve beagle dogs were employed. Blocks of
`22 X 22 mm and 15 X 15 mm (Fig. 1), were inserted subcutaneously
`and intramuseularly in each dog. Serum calcium and phosphate
`levels were monitored at zero time and weekly until sacrifice. No
`rise in serum calcium or phosphate was noted. At
`the time of
`sacrifice, the kidneys were examined by fine—dctail radiography. No
`calcification was noted.
`
`The dogs were sacrificed at varying intervals up to 4 months. At
`sacrifice,
`the regional lymph nodes were not enlarged. Blocks of
`tissue containing the implants were removed and fixed for 24 hr in
`10% buffered formalin.
`In two of the implants, undeealcified sec-
`tions were cut; in four, decalcification was carried out and sections
`cut with the implants in situ.
`In the remainder, the implants were
`
`
`
`Fig. 1. Synthos blocks obtained from the manufacturer.
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`BIODEGRADABLE CERAMIC
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`181
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`removed from the tissue envelope and, following paraflin embedding,
`histological sections of the tissue envelope were obtained. The local
`tissue reaction was extremely benign (Fig. 2). The implant was
`surrounded by and infiltrated with fibrous tissue. A very occasional
`foreign—body giant cell was present, but no other inflammatory cell
`was noted.
`
`In the light of these results, it can be concluded that this material
`does not produce any untoward tissue reaction or any general sys-
`temic reaction.
`It is therefore safe for use in clinical practice.
`Mechanical testing was also carried out on these blocks with the
`aid of a Instron Tester.
`Initial ultimate compressive strength
`varied over a range of 3,000—1,000 psi. This variability is inherent in
`a ceramic and is related to the distribution of imperfections from
`which cracks leading to fracture can grows’) After 4 months in situ,
`this dropped to around 700 psi. Ultimate tensile strength was also
`measured by using diametrical tension testing.
`Initially, this ‘vas
`around 700 psi and dropped to 400 psi after 4 months. The material,
`therefore, does have some useful structural properties, although this
`is a bonus, rather than a requirement, as we envisage using this
`
`
`
`Fig. 2. An occasional foreign-body giant cell can be seen in the soft tissue
`surrounding a block of Synthos, but no other inflammatory cells are present.
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`CAMERON, MACNAB, AND PILLIAR
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`material in orthopedic surgery in a manner similar to a cancellous
`bone graft and not as a structural member.
`When examined with the scanning electron microscope at zero
`time and after 3 months, it was obvious that marked dissolution of
`the periphery of the block had occurred.
`
`BONE INGROWTH
`
`To examine the effect of the ceramic in cancellous bone, a 4.5 mm
`hole was drilled into the metaphyses of the femur in 12 dogs. A
`suitably sized plug of the ceramic was then forced into the hole and
`pushed down into the femoral condyles. The ceramic can be shaped
`readily either with a hand—held rasp or with a high—speed dental burr.
`The dogs were sacrificed at varying times up to 4 months and the
`femurs were removed. Suitably sized sections of bone containing
`the ceramic were cut with a band saw, decalcified, and examined
`histologically.
`Upon insertion, the ceramic filled with blood clot. By 1 week,
`fibrous tissue invasion of the implant had begun. At 2 weeks, the
`implant was completely invaded by fibrous tissue, and some new
`bone formation could be seen around the implant. At 3 weeks, bone
`was seen within the periphery of the implant, and by 4 weeks the
`implant was completely infiltrated with bone (Fig. 3). This bone
`increased in amount until the sixth week, when all the pores were
`completely filled. Thereafter, the bone increased very slowly as the
`ceramic was resorbed.
`
`The reaction to the ceramic was incredibly benign. The bone
`frequently lay in direct apposition with the ceramic (Fig. 4).
`In
`areas where absorption of the ceramic was occurring, a layer of plump
`osteoblasts surrounded the bony trabeculae, and fibroblasts and
`giant cells were found within the ceramic trabeculae.
`At the end of 4 months, although considerable resorption had
`occurred, the ceramic was still obviously present in fair quantities.
`A longer—term experiment will be required to see how long it takes
`for the ceramic to completely disappear, although this is obviously
`size-dependent. The histological appearance suggested that al-
`though passive dissolution of the material doubtlessly occurs, inges-
`tion by giant cells does play a significant role.
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`BIODEGRADABLE CERAMIC
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`Fig. 3. Synthos block completely infiltrated by bony trabeculae. The
`tricalcium phosphate shows up as the granular background. Cortical bone walls
`are seen on either side of the implant.
`
`
`
`
`Fig. 4. Tricalcium phosphate is frequently in direct apposition with bone.
`In areas where active absorption of the ceramic is occurring, the bony trabeculae
`are lined with a layer of plump osteoblasts ; fibrous tissue with an occasional giant
`cell has infiltrated the ceramic trabecula.
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`184
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`CAMERON, MACNAB, AND PILLIAR
`
`As it is conceivable that this material could be used as an onlay
`graft, the method of attachment of the material to cortical bone was
`investigated in dogs. Two dogs were used to test each method of
`fixation and sacrificed at 3 months. Results showed that if the im-
`
`plant was placed outside the periosteum, no bone ingrowth occurred.
`Also, if the implant was placed subperiosteally and held loosely in
`place, no bone growth occurred.
`Instead, a layer of fibrous tissue
`developed between the implant and the bone (Fig. 5).
`If the smooth
`cortical bone was roughened with an osteotome, the tendency for
`bone ingrowth was enhanced. Even when the ceramic was firmly
`fixed to the smooth cortical bone with lag screws, the tendency for
`bone ingrowth was not marked, showing that the cortex must be rough-
`ened to produce raw bleeding bone when this implant is used. When
`the implants were firmly fixed to raw bleeding bone with a lag screw,
`a circumferential wire, or circumferential Dexon 1,
`in every case
`bone ingrowth occurred.
`Fixation was attempted by using an interference fit, that is, drilling
`holes in the bone and shaping the implant so that a tightly fitting
`
`
`
`Fig. 5. The screw held the ceramic loosely against the bone cortex. A layer
`of fibrous tissue is present between the ceramic and bone. The ceramic is com-
`pletely infiltrated by fibrous tissue.
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`BIODEGRADABLE CERAMIC
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`peg could be pushed into the bone. This did not give adequate
`fixation. The peg either broke, or in spite of being initially a tight
`fit, it loosened and fell out after a 1 week period. This method of
`fixation is therefore not recommended.
`
`The final question is, does this material stimulate bone formation;
`that is,
`is it a bone inductor‘? Bone grew laterally from the shaft
`of the femur up to 0.75 cm within the ceramic. This is a greater
`distance than normally occurs if an inert spacer such as Gelfoam is
`placed subperiosteally.
`In two control animals, Gelfoam was placed
`subperiosteally.
`In these dogs,
`lateral bone growth occurred,
`reaching a maximum of 0.4 cm.
`In this sense, therefore, the material
`behaves more like a bone graft than a spacer.
`It is doubtful, how-
`ever, that this should be termed bone induction.
`
`DISCUSSION
`
`It would seem that, at the moment, this material could be used in
`orthopedic surgery to replace bone graft in articular crush fractures
`such as tibial plateau,
`tibial plafond, or os calcis. Similar uses
`would be gap filling in compression arthrodesis, such as rheumatoid
`knee. Under these circumstances, the ceramic would be surrounded
`by living cancellous bone and would be rapidly incorporated.
`Another possible use would be the filling of defects left after curet-
`tage of small benign lesions in bone.
`Other uses will require further definitive experiments, but would
`probably include use as a supplement to bone grafting in spinal
`fusion where little autogenous bone is available.
`In summary, it would appear that this material is safe and useful
`either in replacing or supplementing bone grafting.
`
`The authors would like to thank Tom Driskell of Miter Inc. for his advice and
`assistance, and Mrs. Marie Wilson for typing the manuscript.
`
`References
`
`I. S. N. Bhaskar, J. M. Brady, L. Getter, M. F. Grover, and T. Driskell, Oral
`Surg., 32, 336 (1971).
`2. D. E. Cutright, S. N. Bhaskar, J. l\I. Brady, L. Getter, and W. R. Posey,
`Oral Surg., 33, 850 (1972).
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`CAMERON, MACNAB, AND PILLIAR
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`3. T. D. Driskell, C. R. I-Iassler, and L. R. McCoy, in Proceedings of the 26th
`ACEMB, 1973, p. 199.
`4. M. P. Levin, L. Getter, and D. E. Cutright, J. Biomed. Mater. Res., 9, 183
`(1975).
`5. A. L. Robinson, Science, 187, 1187 (1975).
`
`Received August 2, 1975
`
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