Successful Mandibular ReconstructionUsing a BMP BioimplantHassan G. Moghadam, DDS*Marshall R. Urist, MD†George K. B. Sandor, MD, DDS*Cameron M. L. Clokie, DDS, PhD*

Toronto, Ontario, CanadaLos Angeles, California

A bone morphogenetic protein bioimplant wasused for primary reconstruction of a 6-cm mandibu-lar discontinuity defect, after a segmental resectionof an ameloblastoma. Radiographic evidence ofnew bone induction was seen at 3 and 9 months,postoperatively. A biopsy was taken at 9 monthsdemonstrated viable new bone formation at the bio-implant site. This is the first reported case using abone morphogenetic protein bioimplant in a human,followed by histological confirmation of new bone.

Key Words: Ameloblastoma, BMP, bioimplant, man-dibular reconstruction

The ability of allogeneic bone implants to in-duce bone formation at a heterotopic sitewas first described by Urist in 1965.1 Hecontinued by demonstrating that this os-

teoinductive potential was produced by a noncollag-enous protein, bone morphogenetic protein (BMP).Bone morphogenetic protein is a mesenchymal celldifferentiation factor, classified as a morphogen, hav-ing an ability to recapitulate the events of embryonicbone formation.1,2 It is recognized as part of thetransforming growth factor beta superfamily,3 alarge multigene family of a cytokines that function toregulate a number of physiological processes.

The BMP subfamily has an identifying pattern ofseven conserved cysteine residues at the mature car-boxy terminal where the activity resides.4 They arelow molecular weight proteins (19 to 30 kDa) with apH of 4.9 to 5.1, and they become activated by plas-mins and other enzymes at pH 2 to 6.5,6 The recent

discovery of the Smad proteins has allowed for abetter understanding of how BMP functions.7 Smadsare required for intracellular signal transduction andreceptor function at BMP receptor sites leading togene transcription.8 The Smad complex may directlyor indirectly initiate transcription of the osteoblast-specific factor-2 gene.8 It has been postulated thatosteoblast-specific factor-2 may stimulate mesenchy-mal stem cells to differentiate into osteoblasts duringdevelopment and bone healing. 9,10

Bone morphogenetic protein is present in mosttissues, including the perichondrial layer around de-veloping ribs, vertebrae, limbs, and the craniofacialskeleton.4,11 Various BMPs and their receptors havebeen detected at fracture sites in rats.12,13 The level ofBMP decreases at the fracture sites as healing pro-gresses from woven to lamellar bone.12 Bone mor-phogenetic protein also plays a role in remodeling ofthe adult skeleton. When osteoclasts resorb bone ma-trix, BMP is released, which provides for the recruit-ment and differentiation of stem cell precursors toform new bone, completing the classic cycle of boneturnover and remodeling. Thus, BMP is involved inbone adaptation, healing, and repair.

Clinical applications of BMP for bone graftinghave recently begun to attract considerable interest.In animal models, BMP has been shown to promotefusion of vertebral bodies and regeneration of os-seous structures including the cranial vault, the man-dible, and the extremities. Toriumi et al. in 1991 dem-onstrated functional regeneration of critical-size, full-thickness defects with BMP implant constructs indog mandibles at 10 weeks and complete bone re-generation at 3 months.14 The efficacy of BMP hasbeen demonstrated for the healing of critical-size de-fects in a number of animal models.15 Some investi-gators have even suggested that BMP can consis-tently induce better bone healing than autogenicbone grafting.16 We now anticipate the efficacy ofBMP implants for human osseous reconstruction

*Oral and Maxillofacial Surgery, University of Toronto, On-tario, Canada; and †Bone Research Laboratory, University of Cali-fornia, Los Angeles, California.

Address correspondence and reprint requests to Dr Clokie, Oraland Maxillofacial Surgery, University of Toronto, 124 EdwardStreet, Toronto, Ontario M5B 1G6, Canada. E-mail: cameron.clokie@utoronto.ca

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with the development of new and improved deliveryvehicles.17,18 These implants may eventually obviatethe need for autogenic bone harvest before recon-struction. Restoration of form and function after tu-mor ablation is one area where these implants willhave a significant impact.

Ameloblastoma is a benign locally aggressive le-sion, which usually affects the mandible and repre-sents 11% of all odontogenic tumors. The treatmentof a large multicystic ameloblastoma of the mandibleusually involves marginal or segmental resection fol-lowed by primary reconstruction.19,20 Traditionally,autogenous bone has been used for the primary re-construction of the resultant mandibular defects.This communication describes a case of a large man-dibular ameloblastoma affecting the ramus and bodyof the mandible that was reconstructed using an al-logeneic bioimplant composed of BMP delivered in ademineralized bone matrix gel.

CASE REPORT

In August 1998, a 40-year-old male patient pre-sented to the Oral and Maxillofacial Surgery Clinic

at the Toronto General Hospital with an 8-monthhistory of left sided lower jaw pain. He was in goodhealth with a medical history significant for Hodg-kin’s lymphoma. He was successfully treated for hislymphoma in 1973, undergoing combination therapy

involving high-dose radiation to his thorax and ad-junctive chemotherapy. His clinical examination re-vealed extensive buccal and lingual bony expansionof the left posterior mandible. Radiographically, amultilocular radiolucent area was seen extendingposteriorly from the second mandibular premolar tothe anterior aspect of the coronoid process (Fig 1).The lesion extended to the inferior border of themandible, and a perforation of the lingual plate wasnoted including extension into the lingual soft tissues(Fig 2).

An incisional biopsy was performed in the leftretromolar pad, which revealed follicular islands ofepithelium surrounded by a connective tissuestroma. The epithelial nests had a central core resem-bling the stellate reticulum of the enamel organ. Asingle layer of tall columnar cells with reverse polar-ity surrounded these nests, resembling ameloblasts.The pathology report was consistent with the diag-nosis of follicular ameloblastoma.

Because of the size of the lesion, the patient wasscheduled for an en bloc resection of the left man-dible with primary reconstruction of the defect. ABMP bioimplant was selected for reconstruction aftertumor ablation because of concerns related to thepotential quality of autogenic bone due to previoustotal body radiation treatment.

After the placement of maxillary and mandibu-lar arch bars, the intraoral gingival defect resulting

Fig 1 Preoperative pan-oramic radiograph dem-onstrating a multilocularradiolucency in the leftmandible, extending fromthe left mandibular secondpremolar to the anterioraspect of the coronoid pro-cess.

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from the biopsy was excised, and the lower left sec-ond premolar was removed. The tumor was ap-proached using an extended submandibular incision.Once exposed, a 2.4-mm locking reconstruction plate(Synthes, Monument, CO) was adapted to the man-dible and secured in place. The plate was then re-moved, and a vertical ramous osteotomy was per-formed from the sigmoid notch of the left mandibleinferiorly to the angle of the mandible. Anteriorly,the osteotomy was placed just distal to the left firstpremolar tooth. The reconstruction plate was thenfixed in place with three screws on either side of thedefect (Fig 3).

The buccal musculature was then sutured to thelateral border of the reconstruction plate. This cre-ated a muscular pocket into which a 10-ml bioim-plant, consisting of a poloxamer-based gel (Dyna-Graft Gel, GenSci Regeneration Sciences, Irvine, CA)and 200 mg of native human BMP (Fig 4), waspacked. The material was sculpted along the medialsurface of the reconstruction plate in an attempt torecreate the form of the lower jaw. To reproduce theinferior border of the mandible, three pieces of allo-geneic bone impregnated with native human BMPwere placed below the reconstruction plate. The me-dial soft tissues were sutured to the inferior aspect ofthe plate sealing the muscular pouch, exposing theBMP to a local blood supply and a source of primi-tive mesenchymal cells. After closure of the wound,maxillomandibular fixation was released. The pa-

tient was discharged from the hospital the day aftersurgery and was seen weekly for the first month andthen had follow-up appointments at 3, 6, and 9months.

Initial clinical and radiographic evidence of newbone formation was seen as early as 3 months (Figs 5and 6). Firm buccal and lingual shelves were pal-pated and, radiographically, areas of radiopacitywere identified above the reconstruction plate. Moreobvious radiographic evidence of bone inductionwas seen at the 6- and 9-month postsurgical appoint-ments (Fig 7). Intraorally, excellent ridge height andwidth was achieved (Fig 8). The soft-tissue reactionto this type of reconstruction was very favorable andhealing was uneventful, with the patient experienc-ing very little postoperative morbidity.

At his 9-month appointment, in an attempt toexamine the quality of bone, the patient consented toa biopsy of the newly formed bone. On exposure ofthe surgical site, solid bone formation was seen in thearea of the reconstruction plate, which was found tobe continuous with both resection margins (Fig 9).Histological examination demonstrated viable bonewith numerous osteocytes beneath an overlyinglayer of connective tissue (Figs 10 and 11).

DISCUSSION

The restoration of mandibular height and width areessential for functional prosthetic rehabilitation after

Fig 2 Preoperative com-puted tomography scandemonstrating the extentof the lesion in the leftmandibular ramus.

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F i g 4 T h e m u s c u l a rpocket in to which a 10-mlbioimplant was placed isshown and consists of apoloxamer-based gel (Dy-naGraft Gel) and 200 mg ofnative human bone mor-phogenetic protein.

Fig 3 The reconstructionplate is shown extendingfrom the proximal seg-ment on the right side ofthe photograph, spanningthe defect to the distal seg-ment at the body of themandible in the premolarregion.

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reconstruction of a significant discontinuity defect ofthe mandible. Proper reconstruction will also ensurethat appropriate facial form is recreated. These ob-jectives were met in this case. Patient morbidity and

length of hospital stay were also significantly re-duced.

The regeneration of an osseous defect has beendescribed as an interplay between three mecha-

Fig 5 A 3-month pan-oramic radiograph dem-onstrates evidence of newbone formation at the bio-implant site.

Fig 6 An intraoral photo-graph demonstrating theridge form at 3 months.

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nisms—osteogenesis, osteoconduction, and osteoin-duction. Osteogenesis refers to the formation of newbone from osteoprogenitor cells transferred into therecipient site.21,22 Osteoconduction defines a process

of new bone formation from host-derived or trans-planted osteoprogenitor cells along a biocompatiblescaffold. This mechanism is responsible for bonegrowth seen along reconstruction plates and other

Fig 7 A 9-month pan-oramic radiograph dem-onstrates radiographic evi-dence of bone inductionthroughout the bioimplantsite.

Fig 8 An intraoral photo-graph demonstrating thebuccal and lingual ridgeform at 9 months.

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biological surfaces. The formation of new bone bythe activation of local mesenchymal cells, which pro-vides for their differentiation into bone-forming cells,is referred to as osteoinduction.1 Autogenic bone isconsidered to be the criterion standard in reconstruc-tive bone grafting because it provides these threebasic components of bone healing— osteoinductive

growth factors, osteogenic stem cells within the bonemarrow, and an osteoconductive hydroxyapatite–collagen matrix.

Autogenous bone grafting, however, has severallimitations. Because of the limited number of donorsites available in the human skeleton, only a finitequantity of bone can be harvested.16 The surgical

Fig 10 Histological ex-amination at 9 monthsdemonstrated viable bonewith numerous osteocytesbeneath an overlying layerof connective tissue (H&E,original magnification×20).

Fig 9 An intraoral photo-graph at 9 months, whichshows the biopsy site.Clinically solid bone isidentified at the bioim-plant site.

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morbidity estimated to be 8% to 10% and includingpain, paresthesia, anesthesia, and infection associ-ated with autogenous bone harvesting may begreater than that experienced at the primary surgicalsite.23 The quality of bone harvested may also vary,depending on the patient and the site of procure-ment.

Alternatively, allografts provide primarily os-teoconduction and, if treated properly, some osteoin-duction. Although disease transmission with al-lografts remains a concern, current rigorousscreening and processing techniques reduce the riskto negligible levels.24,25 Despite these concerns, allo-geneic bone has been used successfully for the man-agement of osteotomy gaps, periodontal defects,maxillary sinus lifts, and as resorbable cribs in con-junction with autogenic bone.

A synthetic bone substitute would overcome theproblems with autogenous and allogeneic grafting.The ideal synthetic bone substitute would mimic na-tive bone. The goal is to create a bone regenerationmaterial that would contain osteoinductive factors,primitive osteoprogenitor stem cells, and an osteo-conductive matrix, providing a favorable environ-ment for the interaction of the cells and factors. This“orthobiologic” bioimplant would ultimately resorband be completely replaced by host bone.

One challenge in developing clinical applica-tions for BMP lies in the discovery of biodegradableexcipients. Delivery vehicles such as collagen, de-

mineralized bone matrix, hydroxyapatite, and poly-lactic and polyglycolic acid copolymers have beenevaluated. Although results with polylactic andpolyglycolic acid copolymers carriers have been in-teresting, they have been shown to not completelyresorb, leaving voids in the newly formed bone. Re-cent work comparing various methods of deliverydemonstrated the superiority of Poloxamer 407(BASF, Parsippany, NJ) as the excipient. Histologicalresults showed that greater than 90% of the implantswere composed of new bone, 28 days after implan-tation when the poloxamer was used as the BMPdelivery vehicle.26

Poloxamer 407 is a block copolymer that acts asa porous microsphere having a low surface tension.When used as a delivery vehicle for BMP, bone in-duction is activated by BMP release, which is regu-lated by the water content of the tissue. This allowsfor the sustained release of BMP from the implant,which is ultimately resorbed and replaced by thenewly induced bone. Another interesting feature ofthe poloxamers is their reverse thermal characteris-tics. These allow the bioimplant to become more vis-cous at body temperature, providing an opportunityto mold the bioimplant into the desired form.27

Successful mandibular reconstruction wasachieved using a BMP bioimplant consisting of na-tive human BMP delivered by demineralized bonematrix suspended in a poloxamer gel. In this case,both functional and esthetic results were achieved.

Fig 11 Histological ap-pearance of specimen at 9months demonstrated newbone formation associatedwith vascular channelsand an area of residual de-mineralized bone matrix,identified by the empty os-teocytes lacunae (H&E,original magnification×60).

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Radiographic and histological evidence of new bonewas demonstrated. Although this case has shown en-couraging results, more clinical studies are needed totruly understand the behavior of BMP in reconstruc-tive surgery. Long-term results and the predictabilityof this type of reconstruction in humans are still un-known. Continued developments in the understand-ing of the molecular biology of BMP and ongoingprogress in the field of drug delivery will make thedevelopment of the ideal bone substitute attainable.

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