Protein-Signaled Guided Bone Regeneration Using Titanium Mesh and Rh-BMP2 in Oral Surgery: A Case Report Involving Left Mandibular Reconstruction after Tumor Resection.

Abstract

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein approved for use in oral and maxillofacial defect reconstruction. Growth factors act as mediators of cellular growth on morphogenesis and mythogenesis phases. Utilized as recombinant proteins, these growth factors need the presence of local target cells capable of obtaining the required results. This cell population may be present at the wound site or added to scaffolding material before implantation at the surgical site.The aim of this study is to evaluate the clinical and radiographic results of a reported case with a large bone defect, treated with an absorbable collagen sponge, rhBMP-2 and a titanium plate and mesh. The Authors want to report a case which shows the resulting effectiveness of the rhBMP2 action regarding a large, mandibular defect reconstruction. This case also shows how the removal of a rare tumor such as a ghost cell tumor of the jaw may be treated without harvesting bone from another body site. A quick diagnosis of the lesions is important in order to perform the most suitable treatment. The Authors also underline the clinical and histological steps to insure the correct treatment is carried out to solve the case.Moreover, from results obtained from this case, it is possible to highlight several clinical benefits for the patient by adding rhBMP-2 to the common allograft to not only have alveolar reconstruction defects and sinus floor augmentation, but also to have alveolar cleft reconstruction and to treat segmental defects.

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The Open Dentistry Journal, 2012, 6, 51-55 51

1874-2106/12 2012 Bentham Open
Open Access
Protein-Signaled Guided Bone Regeneration Using Titanium Mesh and
Rh-BMP2 in Oral Surgery: A Case Report Involving Left Mandibular
Reconstruction after Tumor Resection
M. Cicciù1,*, A.S. Herford2, E. Stoffella3, G. Cervino4 and D. Cicciù5
1Human Pathology Department, University of Messina University of Messina School of Dentistry
2Oral and Maxillofacial Surgery Loma Linda University, Loma Linda, CA, USA
3Linda University, Loma Linda, CA, US
4Department of Odontostomatology University of Messina School of Dentistry
5Department of Odontostomatology University of Messina School of Dentistry
Abstract: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive protein approved for use
in oral and maxillofacial defect reconstruction. Growth factors act as mediators of cellular growth on morphogenesis and
mythogenesis phases. Utilized as recombinant proteins, these growth factors need the presence of local target cells capable
of obtaining the required results. This cell population may be present at the wound site or added to scaffolding material
before implantation at the surgical site.
The aim of this study is to evaluate the clinical and radiographic results of a reported case with a large bone defect, treated
with an absorbable collagen sponge, rhBMP-2 and a titanium plate and mesh. The Authors want to report a case which
shows the resulting effectiveness of the rhBMP2 action regarding a large, mandibular defect reconstruction. This case also
shows how the removal of a rare tumor such as a ghost cell tumor of the jaw may be treated without harvesting bone from
another body site. A quick diagnosis of the lesions is important in order to perform the most suitable treatment. The
Authors also underline the clinical and histological steps to insure the correct treatment is carried out to solve the case.
Moreover, from results obtained from this case, it is possible to highlight several clinical benefits for the patient by adding
rhBMP-2 to the common allograft to not only have alveolar reconstruction defects and sinus floor augmentation, but also
to have alveolar cleft reconstruction and to treat segmental defects.
Keywords: BMP2 human protein, bone reconstruction, bone regeneration, oral surgery, titanium mesh.
INTRODUCTION
Recombinant human bone morphogenetic protein-2
(rhBMP-2) is an osteoinductive growth factor that has the
potential to greatly reduce the need for autogenous bone
grafts [1]. Urist demonstrated the capabilities of demineral-
ized bone matrixes to induce ectopic bone formation in a rat
muscle pouch. He first introduced the concept that growth
factors can induce bone formation independently of the bone
tissue condition [2].
The emergence of rhBMP-2 as a viable alternative to
common bone grafts is related to two important clinical chal-
lenges. The first is to eliminate the need to harvest bone from
the iliac crest or other sites when performing oral and maxil-
lofacial reconstruction techniques because of morbidity as-
sociated with these procedures [3]. The second reason is to
enhance the degree of new bone formation, ultimately lead-
ing to positioning of dental implants, for treating several
defects of the facial skeleton [4, 5].


*Address correspondence to this author at the Assistant Professor Human
Pathology Department, University of Messina University of Messina School
of Dentistry; Tel: +00390255032621; Fax: 00390255032513;
E-mail: acromarco@yahoo.it
Autogenous bone has long been considered the “gold
standard”. However, there are significant, potential disadvan-
tages. Probably the greatest potential advantage for using
rhBMP-2 is avoiding the need for graft harvesting thus
eliminating any morbidity associated with it. Complications
of harvesting extra oral bone grafts such as the iliac crest
may occur in as many as 15% to 25% of patients [6-9].
Problems associated with iliac crest bone harvesting are
pain and the risk of significant morbidity. Graft harvesting
complications include increased surgical morbidity from an
additional operative site, including chronic donor site pain,
increased operative time, and additional cost. For larger de-
fects, the quantity of bone available for harvest may be in-
sufficient for larger defects or in patients who have under-
gone previous graft harvests. Summary analysis of prospec-
tive studies has shown that rhBMP-2 is superior to an auto-
graft in obtaining lumbar fusion success [10-12]. Although it
remains to be seen whether this is true for maxillofacial re-
constructions, studies thus far are promising. In studies com-
paring iliac crest bone grafts to rhBMP-2 in cleft palate pa-
tients and patients undergoing a sinus lift procedure, the
groups who received rhBMP-2 performed as well as the
autograft groups [13, 14].

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52 The Open Dentistry Journal, 2012, Volume 6 Cicciù et al.
In contrast to the rhBMP-2 application with absorbable
collagen sponge, transplanted autogenous bone may need to
be resorbed or remodelled before fusing. rhBMP-2 may ac-
celerate the creeping substitution of an allograft by stimulat-
ing an osteoclastic response with an osteoblastic response.
BMP has a role in the regulation of bone turnover via cou-
pled osteoblastic and osteclastic activity and BMP mediated
signals are involved in the osteoclastic resorption [15, 16].
In 2007, the FDA granted approval of rhBMP-2 (Infuse
Bone Graft-Medtronic, Memphis TN®) as an alternative to
autogenous bone graft sinus augmentation and for localized
alveolar ridge augmentations for defects associated with ex-
traction sockets. This approval was based on data from 312
patients enrolled in a total of 5 clinical studies. rhBMP-2 is
contraindicated for patients with a known hypersensitivity to
rhBMP-2 or bovine type I collagen. It should not be used in
the vicinity of a resected tumor, in patients with any active
malignancy, in infected sites or pregnant woman [17].
The use of rhBMP-2 delivered to a surgical site in com-
bination with an absorbable collagen sponge has been inves-
tigated in preclinical and clinical studies of localized alveolar
grafting as well as sinus floor augmentation prior to im-
plants. A pivotal study indicated that the use of rhBMP-2
provides clinical and radiographic results equivalent to those
after the use of autogenous grafting [18].
The aim of this work is to investigate the clinical and ra-
diographic long-term results of a hemi-mandibular recon-
struction by using rhBMP2, absorbable collagen sponge and
titanium mesh.
CASE REPORT
An 18 year old patient was undergoing orthodontic
treatment by a local dentist. During a visit, the dentist re-
corded a consistent swelling in the mandibular left corpus. A
presumptive diagnosis of vascular malformation was made,
and the patient was referred to the author for management. A
panorex investigation showed a large tissue mass and exten-
sion of the lesion, and a more ominous growth was suspected
(Figs.1, 2, 3).
A biopsy was taken from the lesion and the histological
report showed it to be a Dentinogenic Ghost Cell Tumor
(Fig. 4). The decision was made to manage the local tumor
with en bloc resection and immediate reconstruction by us-
ing an inferior titanium plate, in order to maintain, without
alteration, the mandibular soft tissue space. Moreover,
rhBMP2 and absorbable collagen sponge (ACS) were ap-
plied inside a titanium mesh (Figs. 5-6). The patient was then
placed into a maxillomandibular fixation (MMF) and an in-

Fig. (1). Orthopantomography showed long mandibular circular
lesion involving several lower jaw teeth.

Fig. (2). A significant swelling in the left mandible may be appreci-
ated before the tumor resection.

Fig. (3). Clinical left mandibular swelling.

Fig. (4). Dentinogenic Ghost Cell Tumor Histological features.

Fig. (5). Anatomic tumor extension after the elevated flap.

Fig. (6). Tumor consistence is clear at the resection time.

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Protein-Signaled Guided Bone Regeneration Using Titanium Mesh The Open Dentistry Journal, 2012, Volume 6 53
ferior 2.4-mm locking reconstruction plate (Synthes, Paoli,
PA) was chosen for the mandibular reconstruction. A full-
thickness incision was made in the mucosa along the defect.
An advantage of placing the incision more buccally is that
closure after grafting is much easier. The incision was ex-
tended to the bone. Then, subperiosteal dissection was used
to adequately expose the entire defect. Broad exposure of the
underlying ridge is important as it allows better visualization
of the defect as well as freeing up soft tissue for easier clo-
sure. Important anatomical landmarks (mental nerve) can be
visualized if deemed necessary in order to avoid damage.
Once the underlying ridge was exposed, a mesh was coun-
tered to correct the defect. It is important to overcorrect by as
much as 10-20% as some resorption is expected. Anterior
defects require a curvature of the mesh in order to rebuild a
natural curve of the arch. The underlying ridge is pierced
with a small drill to stimulate bleeding. This accomplishes
faster integration of the graft as well as supplying additional
stem cells to the area. rhBMP-2 was then placed on the ab-
sorbable collagen sponge. A portion of the collagen sponge
was then cut into small 2-3 mm pieces and mixed throughout
a bone allograft (mineralized or demineralized). Next, the
rhBMP-2/absorbable collagen sponge/allograft was placed
into the mesh (Fig. 7). The mesh and graft material were
then secured in place with a minimum of two screws but
preferably more. Monocortical screws were used in the area
of the inferior alveolar nerve in order to avoid nerve damage.
TC and OPT post op were performed (Figs. 8, 9). The post-
operative course was uneventful with the patient doing very
well. On examination of the patient at the 3 month follow up,
clinical palpation of the mucosa overlying the resected area
showed a hard indurated calcifying surface of the regener-
ated bone. The patient exhibited radiographic evidence of
bone formation as early as 3 or 4 months post-operatively,
and mandibular continuity was regained as demonstrated
both clinically and radiographically (Figs. 10, 11). At the 9
month follow up, the titanium mesh was removed and dental
implants were placed in position (Figs. 12, 13).
DISCUSSION
Pre-prosthetic augmentation procedures, including alveo-
lar ridge augmentation, using bone grafts are commonplace.
Jovanovic et al. performed a histologic study of a canine
ridge augmentation with BMP [19]. They found no signifi-
cant difference between implants with rhBMP-2 induced

Fig. (10). A 3-4 months clinical evaluation. A good soft tissue heal-
ing can be appreciated.

Fig. (11). No more swelling is underlined at frontal image 6 months
post op.

Fig. (12). OPT evaluation at 9 month follow up at removing tita-
nium mesh time. Bone regeneration can be appreciated on the left
body mandible.

Fig. (7). Mandibular reconstruction is performed with low titanium
plate, rhBMP-2 and ACS covered by a titanium mesh.

Fig. (8). Post op radiographic evaluation.

Fig. (9). Post op TC evaluation.

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54 The Open Dentistry Journal, 2012, Volume 6 Cicciù et al.
bone compared to resident bone. rhBMP-2 allows installa-
tion, osseointegration, and long term functional loading of
dental implants.
According to a study performed by Degidi et al., titanium
mesh is helpful in maintaining space with large mandibular
and maxillary defects. Moreover, the use of occlusive mem-
branes (resorbable or non resorbable) may prevent vascular
in-growth and decrease the available adult stem cells [20].
The osteoconductivity capabilities of rhBMP-2 have been
widely studied in different bone healing environments. Pre-
clinical and clinical research has demonstrated that rhBMP-2
combined with absorbable collagen sponge can induce new
bone formation. rhBMP-2 has been show to heal critical size
bone defects in animal models as well as clinical trials [21,
22].
The half-life of rhBMP-2 is only minutes in the blood-
stream; thus, it must be administered locally over a period of
time to bleeding bone to stimulate bone induction associated
with new bone formation. The absorbable, collagen sponge
carrier matrix provides a means of delivering rhBMP-2 to
the surgical site and retains the growth factor at the site. It
has a limited ability to prevent soft tissue prolapse into the
defect thus enabling bony vascular growth to occur during
rhBMP-2 induced bone formation [23]. The ACS is type I
collagen derived from highly purified bovine tendon. The
ACS lacks structural stability and is compressed by the soft
tissue walls of the defect. Future carriers with more struc-
tural stability will aid in maintaining the space for optimal
bone formation to occur. The absorbable collagen sponge is
susceptible to compression from the overlying tissue. This
compression problem has meant that other ways to maintain
space should be considered. Options include engineering an
alternative carrier, addition of compressive resistant osteo-
conductive material, supporting the space with a membrane
or mesh, or using screws or implants to “tent up” the tissue.
Combining the rhBMP-2 with a graft extender may improve
the economic feasibility of rhBMP-2 reducing the required
protein dose [24].
Both rhBMP-2 and rhBMP-7 have been studied in thou-
sands of patients and tens of thousands of animal with a high
safety profile [25]. It is estimated that over 500,000 patients
have been treated with rhBMP-2. Low risk, similar to clini-
cal trials leading to approval, can be expected with “on la-
bel” use. Transient increases in antibodies to BMPs, devel-
oped in 5-10% of patients, does not affect bone healing on
first exposure but little is known to-date regarding the effects
of multiple exposures. Carreon et al. studied patients who
were re-exposed to rhBMP for spine surgery [26]. In the
ninety-six patients who had at least 2-spine surgeries using
rhBMP-2, they found no significant difference in the number
of complications between the first and second surgeries.
There were no wound problems or allergic reactions among
the twelve patients who had a third surgery with rhBMP-2.
They concluded that multiple exposures to rhBMP-2 does
not increase the risk of wound infections/problems or result
in clinically detectable allergic reactions.
When used “off label”, there are possible adverse results
that must be balanced against the benefit of using rhBMP-2.
Changing the recommended concentration resulted in incon-
sistent bone formation. If a higher concentration is used,
local edema or fluid connection may occur as has been re-
ported in some cases of anterior cervical discectomy and
fusion using BMP instead of autogenous bone [27]. Adverse
facial edema has also been noted when rhBMP-2 was used
for cranial reconstruction for craniosynostosis [28]. Because
BMPs can accelerate bone resorption in addition to bone
formation, using more resorbable carriers which have not
been carefully tested with them, may result in accelerated
resorption of the bone. As with any new technology, con-
cerns over additional costs of such interventions should be
considered. As discussed by Kuklo et al. there is a compel-
ling argument for the continued use of such technologies, as
the primary outcome measures of union, rate of infection,
and reoperation were all improved with rhBMP-2 in a large
number of patients [29].
Despite the extent of bone formation, there has not been
any evidence of bone formation extending beyond the
boundaries of the defect. The process of induced bone for-
mation is a controlled response to highly concentrated levels
of rhBMP-2. This bone inducing protein is normally present
endogenously in the body and it is likely that normal growth
regulating genes control the growth process and prevent
over-growth.
Even if the use of rhBMP-2 in oral surgery seems to give
predictable and long term results as shown from the large
number of animal studies and clinical trials, several ques-
tions are still unanswered such as:
•
What is the ideal grafting material to combine with
BMPs to enhance bone formation in a specific defect?
•
Does the addition of BMPs to autogenous bone
improve the “gold standard”’
•
Will alloplastic, allogenic, or xenogenic graft material
in combination with rhBMP-2 prove to be superior
than rhBMP-2/ACS alone?
•
Are there other cytokines that will enhance the
activity of BMPs?
As rhBMP-2 is osteoinductive and allografts are osteo-
conductive, it appears logical to combine the two in an effort
to enhance the amount and rate of bone formation. Future
studies will help to shed light on these questions as we con-
tinue to strive to improve our understanding of bone healing.
CONCLUSION
The published literature suggests that rhBMP-2 is clini-
cally effective in treatment of critical size defects in both

Fig. (13). 4 dental implants positioned at 9 month follow up after
tumor resection in order to reconstitute function and aesthetic of the
left mandible area.

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Protein-Signaled Guided Bone Regeneration Using Titanium Mesh The Open Dentistry Journal, 2012, Volume 6 55
extremities as well as in the maxillofacial region. Moreover,
the excellent results of this case report seems to support the
ability of rhBMP-2 to predictably induce new bone forma-
tion at the implantation site. Further study will continue to
support this conclusion and offer definitive proof that
rhBMP-2 & ACS can be a safe alternative to the harvesting
of autograft in maxillofacial reconstruction just as it has been
in orthopaedic applications. rhBMP-2 repair has significant
advantages for the patient: large bone defects do not need
non-oral donor sites or long surgical procedures. In the pre-
sented case, the possibility of using rhBMP-2 significantly
reduced patient pain and discomfort.
Other advantages include shorter stay in hospital, avoid-
ance of gait and sensory disturbance, as well as a decrease in
possible infection and also the size of the scar formation
area. Surgical time is reduced since the surgeon does not
have to harvest autogenous bone from a secondary site.
In the future, the use of exogenous cytokines, particularly
those in the BMPs series, will become common and the re-
generation of osseous defects will likely be carried out as a
clinical outpatient procedure.
CONFLICT OF INTERET
None declared.
ACKNOWLEDGMENT
Authors would like to express their gratitude to Prof Ve-
ronica Gavin, B.Sc; T.E.F.L. for her excellent contribution in
correcting the English language of this manuscript.
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Received: December 28, 2011 Revised: January 30, 2012 Accepted: February 06, 2012
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