For more than a decade, the radiographic and histologic appearance
of a refined calcium sulfate has been studied in various experimental
animal models in our laboratory and in clinical applications. This
report summarizes our institution’s experience with calcium
sulfate as a synthetic bone graft1,
a graft expander (the synergistic combination of calcium sulfate
with demineralized bone matrix)2-4,
and a method for local delivery of antibiotics5-8.
Historically, orthopaedic usage of calcium sulfate was popularized
by Peltier. Clinically, we have used calcium sulfate to treat numerous
osseous lesions and conditions occurring in the axial and appendicular
skeleton, including a variety of benign lesions of bone, osseous
defects following implant removal, corrective osteotomy sites, spinal
fusion sites, graft sites, fracture defects, and osteomyelitic lesions.
Both our research studies and clinical experience have shown consistent
osteoconduction, excellent biocompatibility, and complete resorption
of calcium sulfate, which was replaced by newly formed bone that
ultimately remodeled to be comparable with autogenous bone. The
scientific basis for the use of calcium sulfate, the typical radiographic
and histologic progression of the implanted material, and the indications
and expectations for clinical use are illustrated. Contributions from
orthopaedic surgeons from several subspecialties demonstrate the
use of calcium sulfate in various applications and anatomic sites.
Research
Synthetic bone-graft materials are of clinical interest because of
the morbidity, potential for disease transmission, and procurement
issues associated with autografts and allografts. The purpose of
this study was to evaluate healing after the use of calcium sulfate
as a synthetic bone graft compared with spontaneous healing with
no graft material and healing after use of autogenous bone graft
in a large medullary defect model1.
Methods
Graft materials: The grafts consisted of either
circular 4.7 3-mm tablets of calcium sulfate dihydrate (CaSO4)
or autogenous cancellous bone.
Experimental model: The grafts were implanted
into 13 50-mm cylindrical cavities in a bilateral canine humeral
model.
Experimental design: In seven animals, fifty
tablets of CaSO4 were implanted in the left humerus and 6 cm3 of
autograft was implanted in the right humerus; healing was evaluated
at six weeks. The same protocol was carried out in another seven
animals, but healing was evaluated at twenty-four weeks. In five
animals, fifty tablets of CaSO4 were implanted in the left humerus
and no graft was implanted in the right humerus; healing was evaluated
at six weeks.
Histologic analysis: Undecalcified transverse
sections, cut at sequential 1-cm levels and stained with basic fuchsin
and toluidine blue, were studied by light microscopy. Similar unstained
sections were quantitated with computer analysis of scanning electron microscopic
images.
Results
Radiographic assessment (Fig. 1): The nongrafted
defects were devoid of new bone, and the autografted defects were
filled with new bone. At six weeks after treatment with CaSO4, residual
tablet sites were evident; at twenty-four weeks, no tablets were
visible.
Histologic assessment (Fig. 2): In the group
treated with CaSO4, all defects were filled with new bone and the
tablets were replaced with concentric circular lamellae. At six
weeks there was residual CaSO4 at the central tablet sites, whereas
at twenty-four weeks only minute residual material was seen. In
the group treated with autogenous bone, all defects were filled
with new bone. At six weeks, there was bone formation on the surfaces
of the fragments. At twenty-four weeks, the graft fragments were encompassed
in new bone. The defects that were not grafted were not filled with
bone; there was minimal new bone, only at the margins of the defect.
The amounts of new bone in the three groups at the two time-periods
are shown in Tables I and II.
Discussion
The amount of new bone formed in the defects with CaSO4 was approximately
four times that in the empty defects with spontaneous healing and
equivalent to that found in the defects with autogenous bone. The
pattern of bone formation with the CaSO4 tablets suggested guided
bone formation. The studied form of CaSO4 was found to provide an
osteoconductive substrate with a predictable and consistent rate
of resorption and excellent biocompatibility. The canine humeral defect
model replicated the time-course of CaSO4 tablet resorption and
replacement by bone observed radiographically in our patients.
Clinical Application (Fig. 3)
A twenty-six-year-old woman presented with a large aneurysmal
bone cyst of the proximal part of the humerus. The defect was debrided
with curettage and was filled with OSTEOSET pellets (Wright Medical
Technology, Arlington, Tennessee) without additional graft material.
Progressively, over the next three months, the pellets completely
resorbed and, concurrently, new bone filled the defect.
Research
In this study, CaSO4 was used as a synthetic bone graft alone and
as a graft expander at a 50:50 ratio with autogenous cancellous
bone for spinal fusion following dorsal laminectomy in a canine
model2.
Methods
Graft materials: The defects were treated with
(1) 10 cm3 of autogenous cancellous bone,
(2) 5 cm3 of autogenous bone and twenty-five
circular 4.7 3-mm tablets of CaSO4, (3) fifty CaSO4 tablets alone,
or (4) no graft.
Experimental model: A dorsal laminectomy was
performed at the first and second lumbar level and at the fourth
and fifth lumbar level in ten dogs. No fat graft was used. CaSO4
tablets and/or bone was placed directly on the dura. The
defect was filled above the level of the laminae.
Experimental design: Five dogs were treated
with a bone graft at one level and no graft at the other, and five
were treated with bone graft and CaSO4 at one level and with CaSO4
alone at the other. All defects were examined at three months.
Spine analysis: Transaxial and sagittal computed
tomography scans were performed.
Histologic analysis: Undecalcified sagittal
sections were examined.
Results
All animals recovered uneventfully from the surgical procedures
with no neurological deficits, and all walked normally within two
days. The prevalence of osseous fusion as determined from sagittal
sections is shown in Table III. The mean area of the bone fusion
mass, quantitated from transaxial computed tomography images at
the mid-laminectomy levels, is shown in Table IV.
Histologically, autogenous bone was well incorporated at the laminectomy
cut surfaces and throughout the fusion mass, with a well-organized
trabecular pattern and a thin neocortex along the dorsal and internal
canal surfaces. Sites treated with the CaSO4 and autograft mixture
demonstrated a similar pattern of bone development. Defects grafted
with CaSO4 tablets alone had irregular areas of bone formation principally
at the sites of the tablets and at the periphery of the defect,
but centrally there were areas of well-organized fibrous tissue.
The laminectomy defects that were not grafted contained only slight
bone arising from the cut surface of the lamina, and the entire
defect was filled with a highly organized fibrous tissue (Fig. 4).
Discussion
This study indicated that CaSO4, at a 50:50 mixture with autogenous
cancellous bone, can be used as a graft extender. In this model,
the complete dorsal laminectomy with exposure of the cord and no
ancillary internal fixation provided an extreme test for spinal
fusion.
Clinical Application
Case 1. A forty-six-year-old man presented with a history of low-back
pain and degenerative disc disease with spinal stenosis. A laminectomy
and fusion from the third and fourth lumbar level to the fifth lumbar
and first sacral level was performed. A combination of OSTEOSET
pellets (Wright Medical Technology) and cancellous bone chips was
applied bilaterally over the transverse processes. Spinal fixation
plates and screws were applied from the fourth lumbar to the first sacral
level. A solid fusion was obtained by nine months (Fig. 5).
Case 2. A forty-six-year-old man presented, twelve years after a
total hip arthroplasty, with a periprosthetic osteolytic lesion adjacent
to a Harris-Galante acetabular component. The cavity was opened
and was debrided superiorly with curettage and inferiorly and medially
with a high-speed burr through the holes in the acetabular component.
The superior defect was treated with autograft, and the medial and
inferior defects were filled with OSTEOSET pellets. At seven weeks
a majority of the pellets had resorbed, and at three months the
pellets were absent, having been replaced by well-organized trabecular
bone (Fig. 6).
Research
CaSO4 has shown excellent biocompatibility, and demineralized
bone matrix has been used successfully as a graft material in the
clinical setting. The purpose of this study was to evaluate the
combination of these materials in the treatment of bone defects.
Methods
Graft materials: Either circular 4.7 ¥ 3-mm
tablets of CaSO4 and demineralized bone matrix or demineralized
bone matrix, supplied frozen, was used.
Experimental model: The grafts were implanted
into 13 ¥ 50-mm cylindrical defects in a bilateral canine
humeral model.
Experimental design: In seven dogs, 6 cm3 of
demineralized bone matrix was implanted in the right humerus and
fifty tablets of CaSO4 and demineralized bone matrix were implanted
in the left humerus.
Histologic analysis: Undecalcified transverse
sections cut at sequential 1-cm levels were stained with basic fuchsin
and toluidine blue and studied by light microscopy. Computer analysis
of backscattered scanning electron microscopy images of similarly
prepared unstained sections was used to quantify the area fraction
of new bone, excluding identifiable areas of residual CaSO4 and
particles of demineralized bone matrix. The amount of bone on the
side treated with the CaSO4 tablets and demineralized bone matrix
was compared with that on the side treated with demineralized bone
matrix alone. The data were analyzed with paired t tests.
Results
Radiographic assessment (Fig. 7): The defects
treated with CaSO4 and demineralized bone matrix were filled with
new bone, with a few circular densities corresponding to sites of
previous tablets. The density of these defects was comparable with
that of native bone, whereas the density of the defects treated
with demineralized bone matrix only was less than that of the CaSO4-treated
defects and that of native bone.
Histologic analysis (Fig. 8): The defects treated with CaSO4
and demineralized bone matrix had no remaining tablets, trabeculae
were mature, and unmineralized osteoid was rare. The appearance
was similar to that of the defects treated with autogenous bone
graft after twenty-four weeks (Fig. 1). There were few demineralized
bone-matrix particles, and residual CaSO4 was scarce. In the defects
treated with demineralized bone matrix alone, new bone was found
predominantly at the margins and haversian surfaces of the demineralized
bone matrix particles. Associated trabeculae were thinner, and a
large number of demineralized bone matrix particles remained. The
amount of bone in the defects at six weeks in both groups is shown
in Table V.
Discussion
Tablets of CaSO4 and demineralized bone matrix demonstrated excellent
biocompatibility. Bone developed between the tablets, replacing
resorbed tablets with mature bone trabeculae, with little remodeling
activity, and without an adverse inflammatory response. The amount
of new bone formed following grafting with CaSO4 tablets and demineralized
bone matrix was equivalent to the amount of bone formed six weeks
following treatment with autogenous bone graft1,
twenty-four weeks following treatment with autogenous bone graft1, twenty-four weeks following treatment
with CaSO4 tablets1, and in native
bone of untreated humeri.
Clinical Application (Fig. 9)
A sixteen-year-old male athlete presented with a large aneurysmal
bone cyst involving the ilium and the acetabulum. The defect was
curetted and filled with 1800 OSTEOSET pellets (Wright Medical Technology)
and an equivalent amount of demineralized bone matrix. After fifteen
months, the defect was filled with new bone, with reformation of
the subchondral plate of the acetabulum.
Research
The efficacy of calcium sulfate as an osteoconductive medicated
bone-graft substitute has been demonstrated in previous canine and
clinical studies from our institution5-8.
This study was performed to investigate the local and systemic effects
of the maximum prescribed dose and 1.8 times the maximum prescribed
dose of tobramycin delivered by calcium sulfate tablets implanted
in an osseous defect model. The maximum prescribed dose is 10 mg/kg
in humans and 20 mg/kg in canines (surface area conversion).
Methods
Tablet resorption and bone response were assessed radiographically
and histologically. Local tobramycin levels were measured by medullary
aspiration. Systemic tobramycin levels as well as serum chemistry,
hematology, and coagulation parameters were also determined.
Graft material: Circular 4.7 3-mm tablets of
CaSO4 loaded with 10% tobramycin (by weight) were implanted.
Experimental model: The grafts were implanted
into 13 100-mm cylindrical cavities in a bilateral canine humeral
model.
Experimental design: With use of a randomization
scheme, five dogs received CaSO4 loaded with the maximum prescribed
dose of tobramycin (102 tablets [nominally]) and
five received CaSO4 loaded with 1.8 times the maximum prescribed
dose of tobramycin (184 tablets [nominally]);
the defects were assessed at twenty-eight days.
Results
Radiographically, tablets that were visible postoperatively decreased
in density and then became undetectable at twenty-eight days, while
the medullary defects appeared to fill with new bone (Fig. 10). Histologically,
the resorbed tablets were replaced by concentric layers of thin
osseous trabeculae (Fig. 11). The two drug dosages exhibited
similar local and systemic profiles. Serum chemistry, hematology,
and coagulation parameters remained within normal limits throughout
the study (Fig. 12).
Discussion
As evidenced in this study, CaSO4 is effective as an osteoconductive
medicated bone-graft substitute; it achieves a predictable local
response and long-term release of the drug over weeks without adverse
systemic effects and with undetectable systemic levels after twenty-four
hours. The lack of adverse systemic effects was supported by no
adverse elevations in serum chemistry parameters or abnormal pathological
findings at necropsy. This indicates a safe and effective method for
local antibiotic treatment and dead-space management. In a previous
study in which tablets containing 2% and 4% tobramycin
were used, an increased concentration of the drug resulted in a
concurrent local and systemic increase, as might be expected5. This was further accentuated in
our study, in which a higher concentration (10%) of tobramycin
led to even higher local and systemic levels. A dosage effect was
demonstrated in our study, with an increasing number of tablets
correlating to increased systemic and local levels. Regardless of
the concentration of the drug in the tablets or the number of tablets
used, systemic levels dissipated to undetectable limits after twenty-four
hours. The present study also indicates that the ability of calcium
sulfate to enhance the healing of large medullary defects, as seen
in previous studies1, persists
even in the presence of high local levels of antibiotics.
Clinical Application
In a forty-three-year-old woman with a Staphylococcus
aureus infection of the proximal part of the tibia (Fig. 13, area of involvement
highlighted on the preoperative radiograph), the defect was surgically
debrided and filled with calcium sulfate pellets loaded with tobramycin.
The infection resolved, and the cavity was filled with new bone
by thirty-one months (Fig. 13).
Note: Dr. Richard Berger’s contribution of Case 2 to
the study of calcium sulfate as a bone-graft expander is greatly
appreciated.
TurnerTM, Urban RM, Gitelis S, Infanger S, Berzins A, Hall DJ, Haggard WO,Parr JE. Efficacy of calcium sulfate, a synthetic bone graft material,
in healing a large canine medullary defect. Trans Orthop Res Soc,1999;24: 522. 24522
1999
TurnerTM, Urban RM, Andersson GBJ, Lawrence AM, Igloria RV, Haggard WO,Parr JE. Spinal fusion using synthetic bone graft calcium sulfate
compared to autogenous bone in a canine model. Trans Soc for Biomaterial,1999;24: 90. 2490
1999
KellyCM, Wilkins RM, Gitelis S, Hartjen C, Watson JT,Kim PT. The use of a surgical grade of calcium sulfate as a bone
graft substitute: results of a multicenter trial. Clin Orthop,2001;328: 42-50. 32842
2001
GitelisS, Piasecki P, Turner T, Haggard W, Charters J,Urban R. Use of a calcium sulfate-based bone graft substitute for benign
lesions of bone. Orthopedics,2001;24: 162-6. 24162
2001
[PubMed]
TurnerTM, Urban RM, Gitelis S, Sumner DR, Haggard WO,Parr JE. Antibiotic delivery from calcium sulfate as a synthetic
bone graft in a canine bone defect. Trans Soc for Biomaterial,1998;21: 111. 21111
1998
Turner TM, Urban RM, Gitelis S, Lawrence-Smith
AM, Hall DJ, Haggard WO, Parr JE. Delivery of tobramycin
using calcium sulfate tablets to graft a large medullary defect:
local and systemic effects. Sixth World Biomaterials Congress
Transactions. 2000;767.
TurnerTM, Urban RM, Gitelis S, Lawrence-Smith AM, Hall DJ, Haggard WO,Parr JE. Local and systemic effects of tobramycin released from
calcium sulfate tablets used to graft a large medullary defect. Trans Orthop Res Soc,2000;25: 213. 25213
2000
Gitelis S, Piasecki P. The
treatment of chronic osteomyelitis with a biodegradable antibiotic
delivery implant; a clinical study. WPOA 2001