SPINE Volume 31, Number 5, pp 542–547
©2006, Lippincott Williams & Wilkins, Inc.
Adverse Effects Associated With High-Dose
Recombinant Human Bone Morphogenetic Protein-2
Use in Anterior Cervical Spine Fusion
Lisa B. E. Shields, MD,* George H. Raque, MD,* Steven D. Glassman, MD,†
Mitchell Campbell, MD,† Todd Vitaz, MD,* John Harpring, MD,*
and Christopher B. Shields, MD*
Study Design. A retrospective review of patients who
underwent an anterior cervical fusion using recombinant
human bone morphogenetic protein (rhBMP)-2 with an
absorbable collagen sponge (INFUSE?; Medtronic Sofa-
mor Danek, Minneapolis, MN).
Objective. To ascertain the complication rate after the
use of high-dose INFUSE? in anterior cervical fusions.
Summary of Background Data. The rhBMP-2 has been
primarily investigated in lumbar spine fusions, where it
has significantly enhanced the fusion rate and decreased
the length of surgery, blood loss, and hospital stay.
Methods. We present 151 patients who underwent
either an anterior cervical discectomy and fusion (n ?
138) or anterior cervical vertebrectomy and fusion (n ?
13) augmented with high-dose INFUSE? between July
2003 and March 2004. The rhBMP-2 (up to 2.1 mg/level)
was used in the anterior cervical discectomy and fusions.
Results. A total of 35 (23.2%) patients had complica-
tions after the use of high-dose INFUSE? in the cervical
spine. There were 15 patients diagnosed with a hema-
toma, including 11 on postoperative day 4 or 5, of whom
8 were surgically evacuated. Thirteen individuals had ei-
ther a prolonged hospital stay (?48 hours) or hospital
readmission because of swallowing/breathing difficulties
or dramatic swelling without hematoma.
Conclusions. A significant rate of complications re-
sulted after the use of a high dose of INFUSE? in anterior
cervical fusions. We hypothesize that in the cervical area,
the putative inflammatory effect that contributes to the
effectiveness of INFUSE? in inducing fusion may spread
to adjacent critical structures and lead to increased post-
operative morbidity. A thorough investigation is war-
ranted to determine the optimal dose of rhBMP-2 that will
promote cervical fusion and minimize complications.
Key words: rhBMP-2, INFUSE?, anterior cervical
discectomy and fusion, cervical vertebrectomy, cervical
fusion, complications. Spine 2006;31:542–547
Anterior cervical discectomy and fusion (ACDF) is a
widely practiced surgical procedure for the treatment of
cervical spondylosis and disc herniation. This interven-
tion initially used autogenous bone, most commonly
from the iliac crest, as the interbody graft. The morbidity
resulting from graft-site harvest may affect up to 30% of
patients, and include neurologic damage, chronic pain,
and risk of infection.1,2This staggering percentage led to
the use of bone graft substitutes, including homologous
bone and a family of growth factors known as bone
morphogenetic proteins (BMPs).
Both recombinant human bone morphogenetic pro-
tein-2 and -7 (rhBMP-2 and OP-1) have been used in the
clinical setting in place of autogenous bone graft, and for
capable of osteoinduction, specifically, the ability to in-
duce de novo bone formation at a nonbony site.5It has
been studied extensively in lumbar spine fusions using
animal models6–12and in human beings.1,13–17Lumbar
fusion using rhBMP-2 has reduced the operating time,
blood loss during surgery, and hospital stay, and has
reflected a higher fusion rate at 24 months compared to
lumbar fusion using autogenous bone.
The success of a fusion using rhBMP-2 is dependent
on a triad of factors, including site, dose, and carrier
specificity.18The INFUSE? Bone Graft (Medtronic Sofa-
mor Danek, Minneapolis, MN) combines rhBMP-2 with
an absorbable collagen sponge to induce osteogenesis.19
of a type-I collagen sponge enhanced with rhBMP-2 in
combination with a tapered, threaded fusion cage (LT-
lumbar degenerative disc disease.20
Although less attention has been focused on the use of
rhBMP-2 in anterior cervical spine fusions, both ani-
comes. The primary feature was the ability of rhBMP-2
to enhance significantly the rate of fusion without asso-
ciated adverse effects. We reviewed the cases of 151 pa-
tients who underwent either an ACDF or anterior cervi-
cal vertebrectomy and fusion using a higher dose of
INFUSE? than had been previously studied, over an
Materials and Methods
Patient Data. A total of 151 patients underwent either an
ACDF (n ? 138) or vertebrectomy (n ? 13) using INFUSE?
gery, University of Louisville School of Medicine, Louisville, KY.
Acknowledgment date: October 26, 2004. First revision date: Decem-
ber 7, 2004. Second revision date: February 7, 2005. Third revision
date: March 11, 2005. Acceptance date: March 14, 2005.
FDA-approved for this indication and is/are not commercially avail-
able in the United States. No funds were received in support of this
One or more of the author(s) has/have received or will receive benefits
for personal or professional use from a commercial party related di-
rectly or indirectly to the subject of this manuscript: e.g., honoraria,
gifts, consultancies, royalties, stocks, stock options, decision making
Address correspondence and reprint requests to Christopher B. Shields,
of Louisville, Louisville, KY 40292; E-mail: firstname.lastname@example.org
Bone Graft between July 2003 and March 2004. There were 62
men (41.0%) and 89 women (59.0%) included in the study.
The ages ranged between 28 and 80 years, with a mean age of
49.9 years. All individuals had pursued conservative treatment
before surgical intervention. Preoperative imaging studies re-
vealed spondylosis in 112 (74.2%) patients and a disc hernia-
reported: neck pain in 148 (98.0%), arm pain in 136 (90.0%),
arm numbness in 106 (70.2%), and arm weakness in 84 pa-
tients (55.6%). A total of 30 (20.0%) patients had undergone
previous cervical surgical procedures, including an anterior
discectomy in 29 and an anterior vertebrectomy in 1. Numer-
ous behavioral or medical conditions associated with an in-
creased risk during anterior cervical surgery were documented:
cigarette smoking in 59 patients (39.1%), hypertension in 53
(35.1%), diabetes mellitus in 15 (9.9%), rheumatoid arthritis
in 2 (1.3%), Coumadin (Bristol-Myers Squibb Co., Princeton,
NJ) use in 2 (1.3%), and 1 patient each of the following—prior
radiation to the cervical region, factor V Leiden mutation (clot-
ting disorder), hemochromatosis, von Willebrand disorder,
acetylcholinesterase inhibitor deficiency, or fish allergy in 1
Graft and rhBMP-2. Of the 138 patients who underwent an
ACDF, 135 received a resorbable poly(D,L-lactic acid) cage
(HYDROSORB 228; Medtronic Sofamor Danek), with a colla-
gen carrier enhanced with rhBMP-2 within the graft, while 3 pa-
tients received the homologous bone graft (CORNERSTONE?;
Medtronic Sofamor Danek), with the rhRMP-2-laden collagen
carrier inserted in the graft. A titanium mesh cage (PYRAMESH
228 ; Medtronic Sofamor Danek) was used in all 13 individuals
who underwent an anterior cervical vertebrectomy and fusion. A
total of up to 2.1 mg of rhBMP-2 per level in the ACDFs was
reconstituted as a 1.4 mL solution and soaked in a sponge mea-
cm2(0.112 mL solution/cm2). The rhBMP-2 was placed within
the construct in the ACDFs, with a higher amount used in the
anterior cervical vertebrectomy and fusions.
ACDF and Anterior Cervical Vertebrectomy and Fusion. A
right-sided incision was made in the cervical area. An intraop-
erative lateral cervical spine radiograph was used to confirm
the appropriate level or levels. The modified Smith-Robinson
technique was subsequently performed. At completion of the
decompression in the ACDFs, cartilaginous endplates were
decorticated followed by wound irrigation with copious
amounts of bacitracin-containing solution. The cage or graft
was selected, filled with INFUSE?, tapped into the disc space,
and countersunk 1 mm. Additional INFUSE? was frequently
placed lateral and anterior to the graft (under the plate) within
the disc space. An anterior cervical plate (ZEPHYR 228;
radiograph confirmed proper alignment and fixation of the
bone graft and plate. Vocal cord monitoring was used through-
out the surgical procedure.
At completion of the decompression in the anterior cer-
vical vertebrectomy and fusions, the foramina were opened
bilaterally. A PYRAMESH 228 cage was appropriately sized,
cut, and contoured for the vertebrectomy defect. The cage was
packed with a combination of local bone and INFUSE?, and
impacted into the defect. Additional INFUSE? was packed an-
terior and lateral to the cage. Drill sites were formed bilaterally
in the vertebral bodies, and a cervical plate was subsequently
placed with 13-mm screws. An intraoperative lateral cervical ra-
diograph showed appropriate positioning of the plate and cage.
A total of 138 patients underwent either a 1, 2, or 3-level
adjacent ACDF, or a noncontiguous 2-level ACDF (Table
4-level anterior vertebrectomy. The anterior approach
solely was used in 149 patients, while 3 patients under-
went a 2 in 1 procedure, consisting of both anterior and
posterior cervical approaches on the same day. A drain
was surgically placed in 35 (25.4%) of 138 patients who
underwent an ACDF and in 8 (61.5%) of 13 patients
who underwent an anterior cervical vertebrectomy and
fusion. The majority of individuals were released from
the hospital within 24 hours of their surgery.
Hematoma. There were 15 (9.9%) patients diagnosed
with a hematoma after undergoing anterior cervical sur-
gery using INFUSE? (Table 2). Eleven patients were di-
agnosed with a hematoma on the fourth or fifth postop-
erative day, consisting of 7 and 4 patients, respectively.
There were 8 patients who underwent surgical evacua-
4 had undergone a 2-level adjacent ACDF, 2 a 1-level
vertebrectomy, and 2 a 2-level vertebrectomy. There was
while 3 previously underwent a 2-level ACDF. Of the 7
Table 1. A Total of 151 Patients Underwent Either an
ACDF or an Anterior Cervical Vertebrectomy and Fusion
Procedure No. (%)
ACDF (n ? 138)
Anterior vertebrectomy and fusion (n ? 13)
Table 2. Presence of a Hematoma After Anterior
Cervical Spine Fusion
(Previous Anterior Cervical Fusion)
Less than Day 4Days 4 or 5
543High-Dose Recombinant Human Bone Morphogenetic Protein-2•Shields et al
patients diagnosed with a hematoma who did not un-
dergo evacuation of the hematoma, 4 had undergone a
1-level ACDF, 2 a 2-level adjacent ACDF, and 1 a 2-level
noncontiguous ACDF. There was 1 patient who had pre-
viously undergone a 2-level ACDF and another who pre-
7 patients (46.7%) who had a hematoma at the index
Prolonged Hospital Stay (>48 hours) or Readmission for Swal-
lowing/Breathing Difficulties Without Hematoma or Reoperation.
There were 13 (8.6%) patients who had either a pro-
longed hospital stay (?48 hours) (n ? 5) or readmission
to the hospital (n ? 8) after undergoing anterior cervical
surgery using INFUSE? (Table 3). Their complaints in-
cluded dysphagia, respiratory difficulties, and incisional
swelling. There were 6 patients who were readmitted on
either postoperative day 3 or 4. Eight individuals had
undergone a 2-level ACDF, 3 a 1-level ACDF, 1 a 2-level
vertebrectomy, and 2 a 1-level vertebrectomy. Only 1
patient in this category had undergone previous anterior
cervical surgery. There were 3 (23.1%) patients who un-
derwent placement of a drain at the index procedure.
Additional Complications. There were 10 patients (6.6%)
who had a myriad of additional complications after an-
terior cervical surgery using INFUSE?, including syn-
drome of inappropriate secretion of antidiuretic hor-
mone (SIADH), collapse of the upper lobe of the right
lung, Horner syndrome, vocal cord palsy, superficial
Figure 1. Cervical computerized tomography indicates an exten-
sive postoperative hematoma (outlined by arrowheads) in the
retropharyngeal space that displaces the trachea anteriorly at the
level of the allograft INFUSE? construct. The hematoma is pre-
dominantly on the right side, and is 2.0-cm thick, 5.5-cm wide, and
8.5-cm long. The horizontal black radiolucency posterior to the he-
matoma represents a plate artifact. The hematoma was evacuated.
Figure 2. Gadolinium-enhanced cervical computerized tomogra-
phy that indicates extensive symmetrical hemorrhage (arrow-
heads) located anterior to the allograft INFUSE? construct. The
hematoma encircles the carotid arteries (circular enhancing
structures within the hematoma), causing marked anterior dis-
placement of the trachea and esophagus. The hematoma is 4.0-cm
thick, 7.0-cm wide, and 12.0-cm long. The hematoma was evacuated.
Table 3. Prolonged Hospital Stay (>48 hs) or
Readmission for Swallowing/Respiratory Difficulties or
Incisional Swelling Without Evidence of Hematoma
Prolonged Stay or
POD indicates postoperative day.
544 Spine•Volume 31•Number 5•2006
stitch abscess, implant dislodgement, and graft resorp-
tion (Table 4).
The rhBMP-2 has been investigated in lumbar spinal fu-
sions in several prospective randomized human clinical tri-
als since 1997.1,13–17In these previous studies, patients in
boththeinvestigationalgroupswho received rhBMP-2 on
an absorbable collagen sponge (INFUSE? Bone Graft)
iliac crest bone graft had an improvement in clinical out-
come, however, mean operating time, blood loss, and
hospital stay were less in the rhBMP-2 groups.1,13–15,17
Furthermore, the investigational patients had a higher
fusion rate at 24 months.1,13–17Based on clinical data,
the Food and Drug Administration has advised that rh-
BMP-2 be approved as the first complete bone graft sub-
stitute for spinal fusion.5,25
Although the experience with rhBMP-2 in anterior
cervical fusion is far more limited, both animal and hu-
studied the effect of 0, 5, and 50 ?g of rhBMP-2 added to
a porous hydroxyapatite graft in goats that underwent a
3-level anterior discectomy. A solid fusion was noted in
goats that received 50 ?g of rhBMP-2. Zdeblick et al23
studied the effect of a cervical intervertebral device filled
with either autogenous bone graft or rhBMP-2 in 21
Alpine goats that underwent a 3-level ACDF. They re-
ported a higher arthrodesis rate and accelerated bone
formation in the group treated with a rhBMP-2-filled
BAK device compared to the groups that underwent
placement of an autogenous bone-filled BAK device that
was either a standard titanium device or hydroxyapatite-
Baskin et al24conducted a human pilot study in ante-
rior cervical discectomy and interbody fusion. The inves-
tigational group received a fibular allograft containing a
rhBMP-2-laden collagen carrier followed by placement
of an anterior cervical plate. The control group received
a fibular allograft filled with cancellous iliac crest au-
tograft followed by plating. The 33 patients underwent
either a 1-level or 2-level arthrodesis. Both groups had
significant improvement in both neck and arm pain, as
well as a 100% fusion rate at 6 months. The patients in
the rhBMP-2 group avoided the pain, scarring, and mor-
bidity associated with harvesting bone from the iliac
Important differences exist in both rhBMP-2 dose and
delivery mechanism between the technique used in the
study by Baskin et al24as compared to our cases. Baskin
et al24used 0.4 mL (0.6 mg) of reconstituted rhBMP-2
solution distributed on a 1.5 ? 2.5-cm sponge within the
bone graft per level of the fusion. In our study, up to 2.1
mg of rhBMP-2 per level was reconstituted as a 1.4 mL
One sponge per level was used in the ACDFs that was
placed within and occasionally on the lateral surface of a
resorbable cage. In this respect, the surface area of the
solution/cm2) per level. The concentration of Baskin
et al’s and our rhBMP-2 mixture was nearly identical.
study during the anterior vertebrectomies and fusions
compared to the ACDFs. The relevance, if any, of using a
resorbable cage for the ACDFs in our study versus a
Smith-Robinson style interbody allograft as used in the
study by Baskin et al24is unknown.
The anterior surgical approach for the treatment of
neural compression by either a disc herniation or osteo-
phyte has gained in popularity and is associated with a
low postoperative morbidity (approximately 3%).26A
compilation of reports representing more than 700
cases of anterior cervical fusion showed that the most
frequent postoperative complications included dyspha-
gia, hoarseness, and hematomas.27The incidence of dys-
phagia after ACDF has varied between 11% and 67%.28
swallowing complaints after anterior cervical fusion, with
the majority of patients recovering within 2 months. Ra-
diologic evidence of dysphagia was significantly associ-
was not related to surgical level, instrumentation, or op-
sient in 8% of patients and permanent in 2%.29
Tew and Mayfield30presented the incidence of com-
plications of 500 surgical procedures with the anterior
cervical approach as: recurrent laryngeal palsy, 4 cases,
hematoma, infection, and Horner syndrome. Although
the reported incidence of recurrent laryngeal nerve palsy
is approximately 1%, it has been reported as high as
or resorption,32a dural tear and cerebrospinal fluid
leak,25or a superficial or deep wound infection.33,34
Table 4. Complications After Anterior Cervical
Spine Fusion Besides Hematoma or Swallowing/
Collapse of right
upper lobe of
Vocal cord palsy
Vocal cord palsy
(2 in 1)
3 1-Level ACDF 1-Level ACDF
8 2-Level vertebrectomy
9 1-Level ACDF
101-Level ACDF1-Level ACDF
545High-Dose Recombinant Human Bone Morphogenetic Protein-2•Shields et al
In this series, a total of 35 (23.2%) patients had com-
plications after undergoing an anterior cervical fusion
using INFUSE?. Although the lack of a prospective de-
sign and concurrent control group is an obvious short-
coming of the study, this rate of complications is mark-
edly higher than either historical literature controls or
our anecdotal clinical experience. The complications
seen in 28 of these patients are most likely related to the
use of high-dose INFUSE?. Specifically, hematomas that
occurred both more frequently and after the immediate
difficulties, and dramatic neck swelling beyond the area of
the incision, represented a different clinical presentation
not appear to be related to the use of INFUSE?, including
the SIADH, collapse of a lung, Horner syndrome, hoarse-
lodgement, and graft resorption.
There were 15 patients who had a hematoma after
undergoing an anterior cervical fusion augmented with
high-dose INFUSE?. Eleven individuals were diagnosed
with the hematoma on postoperative days 4 or 5. There
were 11 cases that were ACDFs, and 4 were anterior
vertebrectomies and fusions, reflecting 7.9% of the total
ACDFs and 30.8% of the total vertebrectomies. This
finding may be a result of the higher amount of INFUSE?
placed within and beside the cage during the vertebrec-
tomy procedure. A prior ACDF may also serve as a po-
tential risk factor. There were 6 individuals diagnosed
with a hematoma who had previously undergone an an-
terior cervical fusion, including 2 with a 1-level ACDF
and 4 with a 2-level ACDF. Of the 4 patients who un-
derwent a vertebrectomy and fusion, and had a hema-
toma develop after surgery, 3 had previously undergone
a 2-level ACDF. The risk of complications may be con-
siderably increased in patients who undergo an anterior
cervical vertebrectomy and fusion, and who have had a
previous anterior cervical fusion.
A total of 13 patients had complications other than a
hematoma after the anterior cervical fusion, including
swallowing/respiratory difficulties and incisional swell-
ing. These patients either remained in the hospital for
longer than 48 hours after their cervical surgery or were
readmitted to the hospital. There were 11 individuals
who had undergone an ACDF, while 2 underwent an
the hematoma group, in which 6 of the 15 individuals
patient in the nonhematoma group had previously un-
dergone an anterior cervical fusion, consisting of a
1-level ACDF. In addition, only 2 patients in the nonhe-
matoma group underwent an anterior cervical vertebrec-
tomy and fusion compared to 4 individuals in the hema-
The data suggest that the rate of complications seen in
this series may be related to the dose of INFUSE? used.
Baskin et al24used a rhBMP-2 dose of 0.6 mg/level with-
out reported complications, as opposed to the dose of up
to 2.1 mg/level of rhBMP-2 for the ACDF procedures in
this study. Furthermore, a higher percentage of complica-
to surgical technique, the use of a resorbable implant, or
placement of INFUSE? outside of the implant.
Regardless of graft material, the risk of a hematoma
developing may be increased with extensive surgical expo-
sure, such as associated with a vertebrectomy compared to
an ACDF. Furthermore, previous anterior cervical spine
a scar. However, the hematomas associated with high-
dose INFUSE? differ from those resulting as a complica-
tion after anterior cervical fusion without the use of
INFUSE? in that the former are encountered despite the
use of a drain, in a higher frequency, and at a later date
(specifically, postoperative day 4 or 5). Almost half the
patients who had a postoperative hematoma had a drain
placed as a component of their surgical procedure. Cer-
vical computerized tomography may prove beneficial af-
ter surgery to differentiate between hematoma and
edema, yet may be deferred in cases when a patient’s
compromised condition necessitates immediate cervical
The present review represents the largest reported series
treated with an anterior cervical fusion using INFUSE?.
The high complication rate is alarming and warrants in-
tense scrutiny. The favorable effect of INFUSE?, specifi-
cally early osteogenesis, may include an inflammatory
reaction that can dissipate to critical structures within
the cervical area. Although a myriad of complications,
including dysphagia, hoarseness, and hematoma, have
been associated with anterior cervical fusion before the
use of INFUSE?, the rate of complications in this series
implies a causal relationship to the use, or potentially
misuse, of INFUSE?. This study emphasizes the risk as-
sociated with application of new technologies in areas in
which extensive clinical experience is not available. Fur-
ther investigation is necessary to determine the optimal
surgical technique and dose of rhBMP-2 that will effec-
tively enhance anterior cervical fusion, but minimize
● The rhBMP-2 promotes bone formation and en-
hances the rate of spinal fusion.
● This study raises the possibility that the use of
up to 3.5 times the previously published dose of
INFUSE? may lead to postoperative morbidity,
such as hematomas, dysphagia, and excessive
edema, after anterior cervical fusion.
warranted to decrease the likelihood of complica-
tions after anterior cervical fusion.
546Spine•Volume 31•Number 5•2006
Acknowledgment Download full-text
The authors thank J. Timothy Burger, MD, and Yi Ping
Zhang, MD, for their contributions to this study. The
authors also thank Norton Healthcare and the Kentucky
Spinal Cord and Head Injury Research Trust for their
support. Dr. Christopher B. Shields holds the Norton
Hospital Chair in Neurosurgery.
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547 High-Dose Recombinant Human Bone Morphogenetic Protein-2•Shields et al