off-label use of recombinant human bone morphogenetic protein-2

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J Oral Maxillofac Surg66:1417-1425, 2008

Off-Label Use of Recombinant HumanBone Morphogenetic Protein-2 (rhBMP-2)for Reconstruction of Mandibular Bone

Defects in HumansTodd G. Carter, DMD,* Pardeep S. Brar, DMD,†

Andrew Tolas, DDS,‡ and O. Ross Beirne, DMD, PhD§

Purpose: The off-label use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for thetreatment of mandibular bone defects was evaluated in 5 patients. The rhBMP-2 was used as an alternativeto autogenous bone grafting.

Patients and Methods: A total of 5 patients had mandibular defects reconstructed with rhBMP-2, 1.5mg/mL, soaked collagen sponges alone or in combination with bone marrow cells and allogeniccancellous bone chips. Four of the patients had mandibular continuity defects and the fifth patient had2 large bone cavities following removal of dentigerous cysts. Radiographs and clinical examinations wereused to evaluate healing. The longest patient follow-up was 22 months after reconstruction.

Results: Radiographic and clinical assessments revealed bone regeneration and restoration of themandibular defects in 3 of the 5 patients. The rhBMP-2 failed in 2 patients with continuity defects. Bothpatients with failed rhBMP-2 grafts were successfully repaired using autogenous harvested from the iliaccrest.

Conclusion: Mandibular bone defects can be successfully reconstructed using rhBMP-2 soaked spongeswith and without including bone marrow cells and allogenic bone. Further studies are needed todetermine the ideal combination of components that will predictably and reliably regenerate bone indifferent types of bone defects.© 2008 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 66:1417-1425, 2008
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econstruction of large osseous mandibular defectsue to pathology or trauma remains a challenge. Au-ogenous corticocancellous bone grafts, bone graftubstitutes, microvascular tissue transfer, and distrac-ion osteogenesis are among the numerous tech-

*Private Practice, Wailuku, HI; and Formerly, Chief Resident,

niversity of Washington, Department of Oral and Maxillofacial

urgery, Seattle, WA.

†Chief Resident, University of Washington, Department of Oral

nd Maxillofacial Surgery, Seattle, WA.

‡Private Practice, Kent, WA; and Clinical Associate Professor,

niversity of Washington, Department of Oral and Maxillofacial

urgery, Seattle, WA.

§Professor and Chair, University of Washington, Department of

ral and Maxillofacial Surgery, Seattle, WA.

Address correspondence and reprint requests to Dr Beirne: Univer-

ity of Washington, Department of Oral and Maxillofacial Surgery, Box

57134, Seattle, WA 98195-7134; e-mail: [email protected]

2008 American Association of Oral and Maxillofacial Surgeons

278-2391/08/6607-0015$34.00/0

moi:10.1016/j.joms.2008.01.058

1417

iques advocated to address the problem. The diver-ity of techniques is an indication of the difficulty ofandibular reconstruction. Despite the many advan-

ages of autogenous grafts, disadvantages including do-or site morbidity, limited availability of donor tissues,nd limitations on graft shape and contour remain.1-6

Clinical applications of the inductive capacity ofone morphogenetic proteins (BMP) are increasinglyhowing the potential of this technology. Successfulunctional regeneration of critical size defects in theanine model was first reported in 1991.7 The efficacyf recombinant human bone morphogenic protein-2rhBMP-2) in 3 subhuman primate models was shownn resection defects in both young and old monkeys,s well as in ostectomy-created simulated bilateralaxillary cleft defects.8 Seto et al9 showed successful

egeneration of segmental mandibular defects in arimate model using rhBMP-2 in a polyglycolic co-

actic acid carrier along with varied amounts of autog-nous bone marrow.The first reported human application of BMP in the
andible was reported by Moghaden et al in 2001.10
mailto:[email protected]

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1418 rhBMP-2 IN TISSUE-ENGINEERED BONE GRAFTS

hey reconstructed a 6-cm mandibular resection de-ect after removal of an ameloblastoma. The defectas reconstructed with a poloxamer-based gel con-

aining 200 mg of native human BMP prepared fromllogenic cortical bone and allogenic bone pieces.one formation was observed at 3 months and in-reased over 9 months of follow-up. A biopsy carriedut at 9 months showed viable bone with numeroussteocytes.A group of investigators used a heterotopic com-

osite graft in minipigs. They combined recombinantuman osteogenic protein 1 (rhOP-1) with xenogenicone mineral in a titanium scaffold. These constructsere inserted into a latissimus muscle pouch to de-

elop a heterotopic composite graft.11,12 They ap-lied this technique to a human patient in 2004.13

The purpose of this study is to present our experi-nce with an off-label use of a commercially availablehBMP-2 (Infuse Medtronic-Sofamor Danek USA, Mem-his, TN) for the reconstruction of mandibular boneefects. We present 5 cases of orthotopic mandibulareconstruction that show the possible use of rhBMP-2or bone tissue engineering in patients with significantony defects.

eport of Cases

CASE 1

A 42-year-old female presented to the emergencyepartment at Harborview Medical Center (HMC) af-er an assault by a male acquaintance. Clinical andadiographic evaluation showed an open and dis-laced left mandibular angle fracture involving therupted left mandibular third molar. The nearlyvulsed third molar was removed immediately due tospiration risk. The patient was treated initially withn intraoral open reduction and internal fixationORIF) using a 2.0-mm plate at the superior bordernd maxillomandibular fixation (MMF). She did noteturn until 6 weeks after repair of her fracture. She

IGURE 1. Case 1. Panoramic radiograph shows a fibrous uniont the fractured left angle of the mandible.

barter et al. rhBMP-2 in Tissue-Engineered Bone Grafts. J Oralaxillofac Surg 2008.

ad removed the MMF and reported eating hardoods. She refused intervention and did not returnntil 5 months after the fracture repair.When she returned, she had an infection with non-

nion of the fracture. The hardware was removed, theracture was debrided, and a reconstruction plate waslaced through an extraoral submandibular approach.he did not return for routine evaluations, and even-ually her lower left second molar had to be removed.ecause of continued discomfort and paresthesia, theeconstruction plate was removed and a fibrous unionith proximal segment migration at the fracture was

vident (Fig 1). The infection resolved and she agreedo reconstruction of the defect with rhBMP-2 to avoidossible morbidity associated with harvesting a boneraft from the iliac crest.She was placed into MMF; the fibrous union and

nvolved bone was excised through an extraoral sub-andibular approach; and a 2.4-mm locking recon-

truction plate was applied. The defect was recon-tructed with a total of 8.4 mg of rhBMP-2 (Infuseedtronic-Sofamor Danek USA) reconstituted as 1.5g/mL solution and absorbed onto absorbable colla-

en sponges (ACS) following the manufacturer’s rec-mmendations. The rhBMP-2 collagen sponges weresed to fill the bony defect and were enclosed withinhe periosteal envelope (Fig 2). The excised bone wasultured and grew 1� coagulase negative Staphylo-occus and 1� Propionibacterium. Her postopera-ive course was remarkable for significantly more softissue swelling than is usually present after traditionaleconstruction with autogenous bone. The patient’shite cell count was not elevated and an aspiration

nd culture of a small quantity of fluid that was col-ected was negative for microorganisms.

The patient did not return until 8 months after theeconstruction. She presented complaining of rightacial swelling and pain from a retained nonrestorableight maxillary first molar. She reported that 1 month

IGURE 2. Case 1. Postoperative panoramic radiograph ob-ained after reconstruction of the mandibular defect using rhBMP-2.

arter et al. rhBMP-2 in Tissue-Engineered Bone Grafts. J Oralaxillofac Surg 2008.

efore presenting for evaluation she heard a loud

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rack on the left while chewing. Panoramic radio-raph showed fracture of the hardware and absencef bone regeneration in the left mandibular defectFig 3). An autogenous corticocancellous iliac crestone graft was used to reconstruct her mandibularefect successfully.

CASE 2

A 43-year-old male presented to the HMC emer-ency room with a complaint of facial pain after anssault. Clinical and radiographic evaluation showedn open right mandibular angle fracture involving theandibular right second molar. He was treated ini-

ially with ORIF of his mandible using a superiororder 2.0-mm plate and MMF. The mandibular rightecond molar and periodontally involved opposingaxillary second and third molars were extracted. He

eturned to the clinic 10 days postoperatively with noMF and broken hardware. The failed fixation plateas removed and a 2.4-mm locking reconstructionlate, which was placed through an extraoral sub-andibular approach, was used to stabilize the frac-

ure (Fig 4). He returned 2 weeks later with an infec-

IGURE 3. Case 1. Panoramic radiograph showing the fracturedeconstruction plate and failure of rhBMP-2 reconstruction.


IGURE 4. Case 2. Radiograph showing ORIF right angle fracturef the mandible with a 2.4-mm locking reconstruction plate.


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ion that required incision and drainage (I&D). Theatient left the hospital against medical advice imme-iately after the treatment. He periodically returnedo the emergency department and affiliated clinicseeking antibiotics and pain medications for a pro-ressing infection of the right mandible (Fig 5). Threeonths after the I&D he returned and agreed to

urgical intervention to resolve the infection. He hadegmental resection of necrotic bone and excision of autaneous sinus tract (Figs 6, 7).After 1 month of uneventful healing, reconstruc-

ion of the large continuity defect was planned. Theatient was concerned about autogenous bone graftonor site morbidity and agreed to reconstructionith rhBMP-2. Because, in case 1, rhBMP-2 absorbedn a collagen sponge alone failed to regenerate bone,utogenous bone marrow and allogenic bone wereombined with the rhBMP-2 impregnated collagenponges to increase the osteogenic potential of theraft.Under general anesthesia the patient’s left iliac

rest was cannulated with an intraosseous infusion

IGURE 5. Case 2. Panoramic radiograph of the mandible withsteomyelitis at the right fracture.


IGURE 6. Case 2. Photograph showing the segmental resectionf the right mandible stabilized with a 2.4-mm reconstruction plate.


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atheter (Dieckmann infusion needle) and 10 cc ofarrow was aspirated (Fig 8). Allogenic cancellous

one chips (Northwest Tissue Center, Seattle, WA)ere allowed to soak in the marrow aspirate while

he recipient bed was prepared (Fig 9). The mandib-lar site was reopened via a submandibular approachnd a recipient bed was created with careful atten-ion to avoid intraoral exposure. The adjacent bonyargins were freshened with a curette. The allogenic

ancellous chips with the bone marrow cells wereolled into the rhBMP-2 impregnated collagenponges. A total of 12 mg rhBMP-2 (Infuse Medtronic-ofamor Danek USA) was reconstituted at 1.5 mg/mLnd absorbed onto the collagen sponges following theanufacturer’s recommendations. A rhBMP-2 satu-

IGURE 8. Case 2. Photograph of syringe used to harvest 10 mLf bone marrow from the anterior hip.

IGURE 7. Case 2. Radiograph of the bone defect after segmentalesection of infected bone.



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ated collagen sponge was placed on the medial of theefect and 4 rolls of the combination graft (rhBMP-2,one marrow cells, allogenic cancellous bone) werelaced into the defect. An additional rhBMP-2 satu-ated sponge was placed over the rolls on the lateralspect of the defect (Figs 10, 11).

The patient did well postoperatively and was dis-harged the following morning. Like the first patient,his patient had significantly more swelling than issually observed with an autogenous free bone graft.panoramic radiograph at 2 months postoperatively

hows induction of bone growth within the defect.ight months after surgery the patient was still expe-iencing persistent pain at the reconstruction site.ecause there was no infection and the continuity ofhe mandible was restored, the reconstruction plateas removed. The defect was bridged with regener-

ted bone (Figs 12, 13). The pain decreased and the

IGURE 9. Case 2. Photograph of absorbable collagen spongesmpregnated with rhBMP-2 wrapped around allogenic bone chipsombined with autogenous bone marrow aspirate.


IGURE 10. Case 2. Photograph of rhBMP-2 soaked collagenponges filled with cancellous bone chips and bone marrow cellslling the bone defect.


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econstruction remained complete 22 months afterlacing the rhBMP-2 tissue engineered graft (Fig 14).

CASE 3

A 42-year-old female was brought to HMC aftereing struck by an automobile. The patient sustainedultiple facial lacerations and a comminuted mandi-

le fracture. During the postoperative period afterepair of the injuries, the patient developed a non-nion of her comminuted mandible fracture (Fig 15).fter discussing the risks and benefits of various tech-iques for reconstruction, the patient decided to pro-eed with mandibular reconstruction using rhBMP-2n combination with autogenous bone marrow cellsnd allogenic cancellous bone.

A total of 10 mL of bone marrow cells was aspiratedrom the patient’s right anterior iliac crest using aieckmann intraosseous infusion needle. Allogenicancellous bone chips (15 mL) (Northwest Tissueenter) were allowed to soak in the bone marrowspirate while the recipient site was prepared. ThehBMP-2 impregnated sponges combined with autog-

IGURE 11. Case 2. Photograph of rhBMP-2 soaked collagenponge placed over the rolled rhBMP-2 soaked collagen spongesontaining bone chips and bone marrow cells.


IGURE 12. Case 2. Panoramic radiograph 8 months after recon-truction with rhBMP-2 soaked collagen sponges combined with au-ogenous bone marrow aspirate and allogenic bone chips.


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nous bone marrow cells and allogenic cancellousone were used to reconstruct the defect as de-cribed for case 2.

The patient, like the previous 2 patients, developedignificantly more facial swelling than is usually seenith autogenous bone grafts. She developed mild cellu-

itis at her incision site, which responded well to oralntibiotics. There was good bone fill in the defect at 18onths (Fig 16).

CASE 4

A 41-year-old female presented to HMC with a com-laint of right facial swelling that was localized to theandible. The mandibular right second premolar had

een extracted at another facility. The patient under-ent incision and drainage in the clinic and was

dmitted for intravenous antibiotics. A computed to-ography scan showed a persistent fluid collection

long with the finding consistent with osteomyelitisf the right mandible. The osteomyelitis extendedrom an area distal to the mandibular right first bicus-id to the angle of the right mandible.

IGURE 13. Case 2. Photograph of bone healing 10 months aftereconstruction.


IGURE 14. Case 2. Panoramic radiograph 22 months aftereconstruction.


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The patient had multiple washouts and debride-ents of her mandible that subsequently requiredartial mandibulectomy of the right mandible afterhe developed a pathologic fracture. The patient wasreated with multiple courses of intravenous antibiot-cs in the hospital as well as with home intravenousntibiotic therapy. The bacterial cultures grew Strep-ococcus milleri at initial presentation and later en-erococcus.

After resection of the mandible, the patient re-uired several I&Ds and subsequent plate removalith placement of an external fixation device. She

eceived hyperbaric oxygen therapy (Fig 17) in addi-ion to the intravenous antibiotic therapy. After 8onths, the patient’s infection resolved completely

nd she underwent reconstruction of her mandibleith rhBMP-2. The rhBMP-2 impregnated collagen

ponges combined with autogenous bone marrowells and allogenic cancellous bone were used toeconstruct the defect as described for cases 2 and 3.he defect was stabilized using the external fixationevice and MMF. Like in the previous cases, the pa-

IGURE 15. Case 3. Panoramic radiograph with arrow at theony defect in the left mandible 3 months after repair of a commi-uted mandible fracture.


IGURE 16. Case 3. Panoramic radiograph showing bone heal-ng 12 months after reconstruction of the bone defect with rhBMP-2ombined with autogenous bone marrow aspirate and allogenicone chips.


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ient developed more soft tissue swelling during themmediate postoperative period than is usually ob-erved with autogenous bone grafts.

Five months postoperatively, the patient had noteveloped a bony union. Her external fixation deviceas removed and she underwent an iliac crest bone

raft reconstruction with placement of a 2.4-mm re-onstruction plate to stabilize her continuity defectFig 18). The patient has continued to have a compli-ated postoperative course requiring the removal ofhe reconstruction plate and multiple I&Ds. The boneraft has healed with repair of the continuity defect.

CASE 5

An 81-year-old male was referred to HMC with aecent history of left facial swelling. A panoramicadiograph showed 2 radiolucent lesions in the man-ible. A lesion on the left was associated with therown of the impacted mandibular left third molarnd one on the right was associated with the crown ofhe impacted right third molar (Fig 19). The patientnderwent an incision and drainage of the swelling

IGURE 17. Case 4. Panoramic radiograph of the defect createdy osteomyelitis at the right mandible. An external fixation device

s stabilizing the mandible.


IGURE 18. Case 4. Panoramic radiograph showing the boneefect reconstructed with an iliac crest bone graft after failure ofhBMP, bone marrow aspirate, and allogenic cancellous bone graft.


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n the left and was placed on oral antibiotics by hisentist. He was referred to Oral and Maxillofacialurgery and when he presented, he had no signs of ancute infection.

A computed tomography scan showed a 4-cm lesionn the right and a 4.5-cm lesion on the left. Both lesionsxhibited minimal bucco-lingual expansion. There wasvidence of perforation at the lingual cortex on the leftide. The inferior border of the mandible on the rightnd left was intact, and there was no evidence of patho-ogic fracture. It appeared that the mandibular left sec-nd molar had a periodontal pocket on the distal sur-ace, which may have caused the infection in the lesionn the left.Because of the history and radiographic findings,

entigerous cysts and odontogenic keratocysts wereigh on the differential diagnosis. The patient agreedo have the lesions enucleated and was informed thatMF may be required after surgery to prevent patho-

ogic fracture.The surgical procedure included application ofaxillary and mandibular arch bars, extraction of theandibular right and left third molars and the leftandibular second molar, enucleation, and curettage

IGURE 19. Case 5. Panoramic radiograph showing 2 well-efined bilateral cystic lesions associated with the mandibular leftnd right third molars.


IGURE 20. Case 5. Panoramic radiograph 2 weeks after enu-leation, curettage of the cysts, and placement of rhBMP-2 soakedollagen sponges.

earter et al. rhBMP-2 in Tissue-Engineered Bone Grafts. J Oralaxillofac Surg 2008.

f both mandibular lesions. The clinical findings wereonsistent with dentigerous cysts. Two large hollowefects remained with a small perforation on the

ingual cortex of the left mandible. The remainingingual bony walls were intact along with a thickortical inferior border. A total of 12 mg rhBMP-2Medtronic-Sofamor Danek USA) absorbed onto colla-en sponges (1.5 mg/mL) was placed into the defects.icrofibrillar collagen (Avitene; CR Bard Inc, Murrayills, NJ) was also placed into the bony cavities to aid

n hemostasis and obliterate the dead space (Fig 20).One week after surgery, the patient was doing well.

nlike the first 4 cases, the patient did not havenexpected soft tissue swelling. The final pathologyeports confirmed that the lesions were dentigerousysts. The patient continued to have an uneventfulostoperative course and has good bone deposition inoth bony cavities (Fig 21).

iscussion

BMPs are mesenchymal cell differentiation factorsnd members of the transforming growth factor-betaTGF-�) superfamily. The BMP subfamily is a group ofow molecular weight proteins (19-30 kDa) with aattern of 7 conserved cysteine residues conferringctivity at the carboxy terminal end.10 The first de-cription of bone morphogenetic proteins is creditedo Dr Marshall Urist. Dr Urist extracted BMPs fromemineralized bone matrix and preserved their induc-ive capacity.14 Recombinant human BMPs were pro-uced successfully in 1988.15

The Food and Drug Administration approvedhBMP-2 (Infuse) for autograft replacement in spinalusions in 2002. In 2004, rhBMP-2 was approved fordjuvant use in open tibia fractures and in March,007, rhBMP-2 was approved “as an alternative toutogenous bone graft for sinus augmentations, andor localized alveolar ridge defects associated with

IGURE 21. Case 5. Panoramic radiograph taken 6 monthsostoperatively after enucleation, curettage, and application ofhBMP. There is increased bone density at both of the defects.


xtraction sockets.”16 The use of rhBMP-2 in the 5

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ases described in this study constituted an off-labelse. The use of rhBMP-2 absorbed onto collagenponges is contraindicated in patients with hypersen-itivity to rhBMP-2 or bovine type I collagen, in areasf active infection, in areas of resected or extantumor, in patients with active malignancy, and inatients who are pregnant or expecting pregnancyithin 1 year.16 In addition, the manufacturer’s phy-

ician labeling recommends a precaution for usinghBMP-2 in patients less than 18 years of age becausehBMP-2 has not been studied in patients who arekeletally immature.16 However, Chin et al17 and Her-ord et al18 have used rhBMP-2 off-label in patientsrom 6 to 18 years old without systemic complica-ions.

The rhBMP-2 is costly. However, because there iso need to harvest an autogenous bone graft, operat-

ng room use and inpatient stay may be shortened,hich could significantly decrease hospital costs andake the cost for reconstruction with rhBMP-2 com-arable to an autogenous graft reconstruction. Com-arative studies need to be done to determine ifhBMP-2 reconstruction is cost-effective relative toutogenous grafting.

The 5 cases described in this study have many simi-arities and differences. Cases 1, 2, and 4 representedatients who were poorly compliant and socio-eco-omically disadvantaged. The third case represented aatient with a comminuted fracture with a residualontinuity defect. The last case represented a patientith benign dentigerous cysts. All of the cases wereithout significant soft tissue deficiency. The recon-

tructions with rhBMP-2 were tolerated well, evenhough there was significant unexpected postopera-ive swelling at the surgical site. Clinicians using rh-MP for anterior cervical spine fusions observed sig-ificantly more swelling when rhBMP-2 was included

n the graft compared with patients that were treatedithout rhBMP-2.19 Like in the first case described in

his report, 3 patients with cervical spine fusions thatad more swelling than typically observed after theusion were evaluated for hematoma or infection, andnly diffuse soft tissue swelling was found. The causef the atypical soft tissue swelling associated withhBMP-2 is unknown.

Several factors contributed to graft failure in the 2atients that did not regenerate bone with thehBMP-2. Case 1 did not have signs of clinical infec-ion at the time of reconstruction with rhBMP-2; how-ver, bacteria were cultured from the resected bone.t is possible that this low level of bacteria may havead a negative effect on bone induction. The successf rhBMP-2 depends on the presence of appropriatetem cells in the local environment to differentiatento bone forming cells. Although the rhBMP-2 was
laced in a periosteal envelope, the chronicity of the t
nfection in case 1 may have decreased the stem cellopulation’s ability to respond to the rhBMP-2. It islso possible that soft tissue swelling compressed theollagen sponges at the graft site and eliminated thepace needed for bone growth. Case 1 may haveeeded a mineralized osteoconductive scaffold tochieve bone fill of the defect.

When cancellous allograft bone was included inases 2, 3, and 4, 2 patients had successful regenera-ion of bone in their continuity defects. The cancel-ous allograft may have acted as an osteoconductivecaffold or a space maintainer to allow bone in-rowth. Hereford et al18 successfully reconstructed aandibular continuity defect in a 12-year-old using

nly the rhBMP-2 absorbed in the collagen and bonelates to provide “tenting” to maintain space for bone

ngrowth.In many reconstructions, rhBMP-2 absorbed to a

ollagen sponge is sufficient to induce bone forma-ion; however, the diffusion of the water solublehBMP-2 from the collagen sponge may be too rapido permit complete bone healing of a large continuityefect.20 The therapeutic outcome of rhBMP-2 de-ends on its quantity, concentration, and time ofpplication.21,22 Therefore, it is important to use anppropriate carrier system for the delivery, retention,nd release of BMPs at the implanted site.23 In addi-ion, it is important to maintain space for bone in-rowth.The cause of graft failure in case 1 cannot be de-

ermined but was likely due to the combination ofhronic infection, significant swelling, limited num-er of stem cells, lack of an osteoconductive scaffold,nd inadequate maintenance of space for bone in-rowth. When autogenous bone marrow and allo-enic cancellous bone were included in the graft forases 2 and 3, there was bone regeneration in theefects. Space maintenance with an allogenic cancel-

ous osteoconductive bone scaffold, as well as thentroduction of mesenchymal stem cells from theone marrow aspirate, may have produced the suc-essful outcome in cases 2 and 3.Case 4 failed even with the inclusion of autogenous

one marrow aspirate and allogenic cancellous boneith the rhBMP-2. This patient had an infection thatas refractory to treatment. She required hyperbaricxygen treatment in addition to long-term antibioticreatment to resolve the osteomyelitis. Even the au-ogenous corticocancellous bone graft from the iliacrest has been slow to heal.A conventional iliac crest graft was chosen for the

econdary treatment in the 2 failed cases because theafety and effectiveness of repeat application ofhBMP-2 has not been established. There are transientncreases in antibodies to BMP-2 in 5% to 10% of patients
reated with rhBMP, which does not affect bone healing

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n the first exposure, but the effects of second exposureo the same BMP have not been established.24

The bone defect in case 5 was significantly differentrom the other 4 cases. The residual mandibular de-ects were not continuity defects. The patient had 2ony cavities, each with 3 walls, after removal of the 2ysts. Bone regeneration was successful with rhBMP-2bsorbed on the collagen sponge alone without theddition of bone marrow aspirate and allogenic bone.he wall of the bone cavity maintained space for bone

ngrowth, and there were probably adequate stem cellsnd osteoblasts at the surgical sites to regenerate bone.

Tissue engineered osteoinductive grafts may some-ay eliminate the need for harvesting corticococan-ellous grafts. A combination of osteoinductive pro-eins, stem cells, and osteoconductive scaffolds willikely be needed to achieve predictable reconstruc-ion of many bony defects whereas other defects maynly require rhBMP-2 absorbed on a matrix. The casesescribed in this study show that it is possible toeconstruct mandibular defects with osteoinductiveroteins produced using recombinant DNA technol-gy. However, more studies are needed to develophe ideal combination of factors that can predictablynd reliably regenerate bone in different defects. Ouresults as well as others10,17-19 show that rhBMP-2 willrobably play a significant role in these tissue engi-eered bone grafts.

eferences1. Ahlmann E, Patzakis M, Roidis N, et al: Comparison of anterior

and posterior iliac crest bone grafts in terms of harvest-sitemorbidity and functional outcomes. J Bone Joint Surg Am84A:716, 2002

2. Heary RF, Schlenk RP, Sacchieri TA, et al: Persistent iliac crestdonor site pain: Independent outcome assessment. Neurosur-gery 50:510, 2002

3. Kalk WWI, Raghoebar GM, Jansma J, et al: Morbidity from iliaccrest bone harvesting. J Oral Maxillofac Surg 54:1424, 1996

4. Beirne OR: Comparison of complications after bone removalfrom lateral and medial plates of the anterior ilium for mandib-ular augmentation Int J Oral Maxillofac Surg 15:269, 1986

5. Marx RE, Morales MJ: Morbidity from bone harvest in major jawreconstruction: A randomized trial comparing the lateral ante-rior and posterior approaches to the ilium. J Oral MaxillofacSurg 46:196, 1988

6. Tayapongsak P, Wimsatt JA, LaBanc JP, et al: Morbidity fromanterior ilium bone harvest. A comparative study of lateralversus medial surgical approach. Oral Surg Oral Med Oral
Pathol 78:296, 1994 2
7. Toriumi DM, Kotler HS, Luxenberg DP, et al: Mandibular re-construction with a recombinant bone inducing factor. ArchOtolaryngol Head Neck Surg 117:1101, 1991

8. Boyne P: Application of bone morphogenetic proteins in thetreatment of clinical oral and maxillofacial osseous defects.J Bone Joint Surg Am 83A:S146, 2001

9. Seto I, Asabina I, Oda M, et al: Reconstruction of the primatemandible with a combination graft of recombinant humanbone morphogenetic protein-2 and bone marrow. J Oral Max-illofac Surg 59:53, 2001

0. Moghadam HG, Urist T, Sandor GK, et al: Successful mandib-ular reconstruction using a BMP bio-implant. J Craniofac Surg12:119, 2001

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2. Terheyden H, Warnke P, Dunsche A, et al: Mandibular recon-struction with a prefabricated vascularized bone graft usingrecombinant human osteogenic protein-1: An experimentalstudy in miniature pigs. Part II: Transplantation. Int J OralMaxillofac Surg 30: 469, 2001

3. Warnke PH, Springer IN, Wiltfang J, et al: Growth and trans-plantation of a custom vascularized bone graft in a man. Lancet364:766, 2004

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