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1.  GMP-level adipose stem cells combined with computer-aided manufacturing to reconstruct mandibular ameloblastoma resection defects: Experience with three cases 
Annals of Maxillofacial Surgery  2013;3(2):114-125.
The current management of large mandibular resection defects involves harvesting of autogenous bone grafts and repeated bending of generic reconstruction plates. However, the major disadvantage of harvesting large autogenous bone grafts is donor site morbidity and the major drawback of repeated reconstruction plate bending is plate fracture and difficulty in reproducing complex facial contours. The aim of this study was to describe reconstruction of three mandibular ameloblastoma resection defects using tissue engineered constructs of beta-tricalcium phosphate (β-TCP) granules, recombinant human bone morphogenetic protein-2 (rhBMP-2), and Good Manufacturing Practice (GMP) level autologous adipose stem cells (ASCs) with progressively increasing usage of computer-aided manufacturing (CAM) technology.
Materials and Methods:
Patients’ three-dimensional (3D) images were used in three consecutive patients to plan and reverse-engineer patient-specific saw guides and reconstruction plates using computer-aided additive manufacturing. Adipose tissue was harvested from the anterior abdominal walls of three patients before resection. ASCs were expanded ex vivo over 3 weeks and seeded onto a β-TCP scaffold with rhBMP-2. Constructs were implanted into patient resection defects together with rapid prototyped reconstruction plates.
All three cases used one step in situ bone formation without the need for an ectopic bone formation step or vascularized flaps. In two of the three patients, dental implants were placed 10 and 14 months following reconstruction, allowing harvesting of bone cores from the regenerated mandibular defects. Histological examination and in vitro analysis of cell viability and cell surface markers were performed and prosthodontic rehabilitation was completed.
Constructs with ASCs, β-TCP scaffolds, and rhBMP-2 can be used to reconstruct a variety of large mandibular defects, together with rapid prototyped reconstruction hardware which supports placement of dental implants.
PMCID: PMC3814659  PMID: 24205470
Adipose-derived stem cells; beta-tricalcium phosphate; bone morphogenetic protein; computer-aided design
2.  Radiological Assessment of Bioengineered Bone in a Muscle Flap for the Reconstruction of Critical-Size Mandibular Defect 
PLoS ONE  2014;9(9):e107403.
This study presents a comprehensive radiographic evaluation of bone regeneration within a pedicled muscle flap for the reconstruction of critical size mandibular defect. The surgical defect (20 mm×15 mm) was created in the mandible of ten experimental rabbits. The masseter muscle was adapted to fill the surgical defect, a combination of calcium sulphate/hydroxyapatite cement (CERAMENT™ |SPINE SUPPORT), BMP-7 and rabbit mesenchymal stromal cells (rMSCs) was injected inside the muscle tissue. Radiographic assessment was carried out on the day of surgery and at 4, 8, and 12 weeks postoperatively. At 12 weeks, the animals were sacrificed and cone beam computerized tomography (CBCT) scanning and micro-computed tomography (µ-CT) were carried out. Clinically, a clear layer of bone tissue was identified closely adherent to the border of the surgical defect. Sporadic radio-opaque areas within the surgical defect were detected radiographically. In comparison with the opposite non operated control side, the estimated quantitative scoring of the radio-opacity was 46.6% ±15, the mean volume of the radio-opaque areas was 63.4% ±20. Areas of a bone density higher than that of the mandibular bone (+35% ±25%) were detected at the borders of the surgical defect. The micro-CT analysis revealed thinner trabeculae of the regenerated bone with a more condensed trabecular pattern than the surrounding native bone. These findings suggest a rapid deposition rate of the mineralised tissue and an active remodelling process of the newly regenerated bone within the muscle flap. The novel surgical model of this study has potential clinical application; the assessment of bone regeneration using the presented radiolographic protocol is descriptive and comprehensive. The findings of this research confirm the remarkable potential of local muscle flaps as local bioreactors to induce bone formation for reconstruction of maxillofacial bony defects.
PMCID: PMC4167331  PMID: 25226170
3.  Computer Simulation Surgery for Mandibular Reconstruction Using a Fibular Osteotomy Guide 
Archives of Plastic Surgery  2014;41(5):584-587.
In the present study, a fibular osteotomy guide based on a computer simulation was applied to a patient who had undergone mandibular segmental ostectomy due to oncological complications. This patient was a 68-year-old woman who presented to our department with a biopsy-proven squamous cell carcinoma on her left gingival area. This lesion had destroyed the cortical bony structure, and the patient showed attenuation of her soft tissue along the inferior alveolar nerve, indicating perineural spread of the tumor. Prior to surgery, a three-dimensional computed tomography scan of the facial and fibular bones was performed. We then created a virtual computer simulation of the mandibular segmental defect through which we segmented the fibular to reconstruct the proper angulation in the original mandible. Approximately 2-cm segments were created on the basis of this simulation and applied to the virtually simulated mandibular segmental defect. Thus, we obtained a virtual model of the ideal mandibular reconstruction for this patient with a fibular free flap. We could then use this computer simulation for the subsequent surgery and minimize the bony gaps between the multiple fibular bony segments.
PMCID: PMC4179365  PMID: 25276653
Surgery, plastic; Head and neck neoplasms; Mandibular reconstruction; Free tissue flaps; Computer simulation
Bone transport distraction osteogenesis (BTDO) provides a promising alternative to traditional grafting techniques. However, existing BTDO devices have many limitations. The purpose of this research was to test a new device, the mandibular bone transport reconstruction plate (BTRP), in an animal model with comparable mandible size to humans and to histologically and mechanically examine the regenerate bone.
Materials and methods
Eleven adult foxhound dogs were divided into an unreconstructed control group of 5 animals, and an experimental group of 6 animals. In each animal, a 34 mm segmental defect was created in the mandible. The defect was reconstructed with BTRP. Histological and biomechanical characteristics of the regenerate and un-repaired defect were analyzed and compared to bone on the contralateral side of the mandible after 4 weeks of consolidation.
The reconstructed defect was bridged with new bone, with little bone in the control defect. Regenerate density and microhardness were 22.3% and 42.6% lower than the contralateral normal bone, respectively. Likewise, the anisotropy of the experimental group was statistically lower than in the contralateral bone. Half the experimental animals showed non-union at the docking site.
The device was very stable and easy to install and activate. After one month of consolidation, the defect has been bridged with new bone with evidence of active bone formation. Regenerate bone was less mature than the control bone. Studies are underway to identify when the regenerate properties compare to normal bone, and to identify methods to augment bone union at the docking site.
PMCID: PMC3181270  PMID: 21601342
Bone transport distraction osteogenesis; microhardness; ultrasound velocity testing; regenerate; bone; mandibular reconstruction; distraction osteogenesis
5.  Skin paddle vascularity of free fibula flap – A study of 386 cases and a classification based on contribution from axial vessels of the leg 
The skin paddle of the free fibula flap receives its vascular supply from septocutaneous perforators, musculocutaneous perforators or from both, and these perforators might originate from the peroneal or posterior tibial vessels or from both. The objective of this study was to classify the skin paddles based on the dominance of vascular contribution by these axial vessels through their different perforator systems.
Materials and Methods:
A retrospective analysis of 5-year data of 386 free fibula flaps used in oro-mandibular reconstruction was done and the skin paddle vascularity was studied. While majority of the skin paddles received their blood supply from the peroneal septocutaneous perforators, a few had their dominant supply from the soleus musculocutaneous perforators in addition to peroneal septocutaneous perforators. In few cases, the soleus musculocutaneous perforators were the sole source of blood supply to the skin paddle. The limitation in this study was the inability to augment the clinical observation with cadaveric study.
The skin paddle of the free fibula flap was classified into four different types (a–d) based on the dominance of vascular contribution by axial vessels of the leg.
The skin paddle of the free fibula flap has reliable blood supply, but a thorough knowledge of the variations in vascular pattern of the skin paddle is required especially to salvage the larger paddles used in the reconstruction complex oro-mandibular defects.
PMCID: PMC3385400  PMID: 22754154
Free fibula flap; musculocutaneous perforators; septo cutaneous perforators; skin paddle; vascular supply
6.  Stabilization of Mobile Mandibular Segments in Mandibular Reconstruction: Use of Spanning Reconstruction Plate 
The fibular free flap is the gold standard for mandibular reconstruction. Accurate 3-dimensional contouring and precise alignment of the fibula is critical for reestablishing native occlusion and facial symmetry. Following segmental mandibulectomy, the remaining mandibular fragments become freely mobile. Various stabilization methods including external fixation, intermaxillary fixation, and preplating with reconstruction plate have been used. We describe a modification to the preplating technique. After wide resection of buccal squamous cell carcinoma, our patient had an 11-cm mandibular defect from the angle of the left mandible to the right midparasymphyseal region. A single 2.0-mm Unilock® (Synthes, Singapore) plate was used to span the defect. This was placed on the vestibular aspect of the superior border of the mandibular remnants before resection. Segmental mandibulectomy was then performed with the plate removed. The spanning plate was then reattached to provide rigid fixation. The fibular bone was contoured with a single osteotomy and reattached. The conventional technique involves molding of the plate at the inferior border of the mandible. This is time-consuming and not possible in patients with distorted mandibular contour. It is also difficult to fit the osteotomized fibula to the contoured plate. In comparison, the superiorly positioned spanning plate achieve rigid fixation of the mandible while leaving the defect completely free and unhampered by hardware, allowing space for planning osteotomies and easier fixation of the neomandible. Using this modified technique, we are able to recreate the original mandibular profile with ease.
PMCID: PMC3578648  PMID: 23997856
mandibular reconstruction; preplating technique; spanning reconstruction plate
7.  The effects of high dose and highly fractionated radiation on distraction osteogenesis in the murine mandible 
The ability of irradiated tissue to support bony growth remains poorly defined, although there are anecdotal cases reported showing mixed results for the use of mandibular distraction osteogenesis after radiation for head and neck cancer. Many of these reports lack objective measures that would allow adequate analysis of outcomes or efficacy. The purpose of this experiment was to utilize a rat model of mandibular distraction osteogenesis after high dose and highly fractionated radiation therapy and to evaluate and quantify distracted bone formation under these conditions. Male Sprague–Dawley rats underwent 12 fractions of external beam radiation (48 Gray) of the left mandible. Following a two week recovery period, an external frame distractor was applied and gradual distraction of the mandible was performed. Tissue was harvested after a twenty-eight day consolidation period. Gross, radiologic and histological evaluations were undertaken. Those animals subjected to pre-operative radiation showed severe attenuation of bone formation including bone atrophy, incomplete bridging of the distraction gap, and gross bony defects or non-union. Although physical lengthening was achieved, the irradiated bone consistently demonstrated marked damaging effects on the normal process of distraction osteogenesis. This murine model has provided reliable evidence of the injurious effects of high dose radiation on bone repair and regeneration in distraction osteogenesis utilizing accurate and reproducible metrics. These results can now be used to assist in the development of therapies directed at mitigating the adverse consequences of radiation on the regeneration of bone and to optimize distraction osteogenesis so it can be successfully applied to post-oncologic reconstruction.
PMCID: PMC3494577  PMID: 22958832
8.  Parathyroid hormone reverses radiation induced hypovascularity in a murine model of distraction osteogenesis 
Bone  2013;56(1):9-15.
Radiation treatment results in a severe diminution of osseous vascularity. Intermittent parathyroid hormone (PTH) has been shown to have an anabolic effect on osteogenesis, though its impact on angiogenesis remains unknown. In this murine model of distraction osteogenesis, we hypothesize that radiation treatment will result in a diminution of vascularity in the distracted regenerate and that delivery of intermittent systemic PTH will promote angiogenesis and reverse radiation induced hypovascularity.
Materials and methods
Nineteen Lewis rats were divided into three groups. All groups underwent distraction of the left mandible. Two groups received radiation treatment to the left mandible prior to distraction, and one of these groups was treated with intermittent subcutaneous PTH (60 μg/kg, once daily) beginning on the first day of distraction for a total duration of 21 days. One group underwent mandibular distraction alone, without radiation. After consolidation, the rats were perfused and imaged with micro-CT angiography and quantitative vascular analysis was performed.
Radiation treatment resulted in a severe diminution of osseous vascularity in the distracted regenerate. In irradiated mandibles undergoing distraction osteogenesis, treatment with intermittent PTH resulted in significant increases in vessel volume fraction, vessel thickness, vessel number, degree of anisotropy, and a significant decrease in vessel separation (p < 0.05). No significant difference in quantitative vascularity existed between the group that was irradiated, distracted and treated with PTH and the group that underwent distraction osteogenesis without radiation treatment.
We quantitatively demonstrate that radiation treatment results in a significant depletion of osseous vascularity, and that intermittent administration of PTH reverses radiation induced hypovascularity in the murine mandible undergoing distraction osteogenesis. While the precise mechanism of PTH-induced angiogenesis remains to be elucidated, this report adds a key component to the pleotropic effect of intermittent PTH on bone formation and further supports the potential use of PTH to enhance osseous regeneration in the irradiated mandible.
PMCID: PMC3758112  PMID: 23643680
Parathyroid hormone; angiogenesis; distraction osteogenesis; radiation; mandible
9.  Pre-operative planning for mandibular reconstruction - A full digital planning workflow resulting in a patient specific reconstruction 
Head & Neck Oncology  2011;3:45.
Reconstruction of large mandiblular defects following ablative oncologic surgery could be done by using vascularized bone transfer or, more often, primarily with simultaneous or delayed bone grafting, using load bearing reconstruction plates. Bending of these reconstruction plates is typically directed along the outer contour of the original mandible. Simultaneously or in a second operation vascularized or non-vascularized bone is fixed to the reconstruction plate. However, the prosthodontic-driven backward planning to ease bony reconstruction of the mandible in terms of dental rehabilitation using implant-retained overdentures might be an eligible solution. The purpose of this work was to develop, establish and clinically evaluate a novel 3D planning procedure for mandibular reconstruction.
Materials and methods
Three patients with tumors involving the mandible, which included squamous cell carcinoma in the floor of the mouth and keratocystic odontogenic tumor, were treated surgically by hemimandibulectomy.
In primary alloplastic mandible reconstruction, shape and size of the reconstruction plate could be predefined and prebent prior to surgery.
Clinical relevance
This study provides modern treatment strategies for mandibular reconstruction.
PMCID: PMC3195208  PMID: 21968330
Mandibular reconstruction; backward planning; patient specific implant; computer-assisted surgery
10.  Successful human long-term application of in situ bone tissue engineering 
Tissue Engineering (TE) and Regenerative Medicine (RM) have gained much popularity because of the tremendous prospects for the care of patients with tissue and organ defects. To overcome the common problem of donor-site morbidity of standard autologous bone grafts, we successfully combined tissue engineering techniques for the first time with the arteriovenous loop model to generate vascularized large bone grafts. We present two cases of large bone defects after debridement of an osteomyelitis. One of the defects was localized in the radius and one in the tibia. For osseus reconstruction, arteriovenous loops were created as vascular axis, which were placed in the bony defects. In case 1, the bone generation was achieved using cancellous bone from the iliac crest and fibrin glue and in case 2 using a clinically approved β-tricalciumphosphate/hydroxyapatite (HA), fibrin glue and directly auto-transplanted bone marrow aspirate from the iliac crest. The following post-operative courses were uneventful. The final examinations took place after 36 and 72 months after the initial operations. Computer tomogrphy (CT), membrane resonance imaging (MRI) and doppler ultrasound revealed patent arterio-venous (AV) loops in the bone grafts as well as completely healed bone defects. The patients were pain-free with normal ranges of motion. This is the first study demonstrating successfully axially vascularized in situ tissue engineered bone generation in large bone defects in a clinical scenario using the arteriovenous loop model without creation of a significant donor-site defect utilizing TE and RM techniques in human patients with long-term stability.
PMCID: PMC4124030  PMID: 24801710
tissue engineering; human application; long term success; large bone defect; arteriovenous loop; clinical translation; regenerative medicine
11.  “Transport Distraction Osteogenesis for Reconstruction of Mandibular Defects”: Our Experience 
Mandibular defects usually involve a combination of osseous and soft tissue deficiency and are among the most challenging problems in maxillofacial surgery, many options are available for mandibular reconstruction. One of the options discussed in literature recently being distraction osteogenesis.
Aim and Objective
The aims and objectives of the study were to evaluate clinically the technique of distraction osteogenesis to reconstruct mandibular defects, using indigenous transport distractors, and to evaluate the efficacy of Indigenous transport distraction osteogenesis device.
Materials and Methods
A prospective, experimental study was designed to examine the use of transport distraction osteogenesis in the treatment of defects of the mandible. Four patients with defects of the mandible were subjected to distraction osteogenesis with indigenously manufactured distraction device. The regenerate was assessed clinically and radiographically.
The results showed that the regenerate was clinically as hard as the adjacent unaffected mandible and radiologic evidence of bone regeneration was observed. The major advantage being regeneration of hard tissue and soft tissue components without the morbidity of donor site, so that functional rehabilitation of the patient is possible.
Thus from our study it is shown that transport distraction osteogenesis using indigenous distractors is a reliable yet affordable option for reconstruction of mandibular defects.
PMCID: PMC3177527  PMID: 22654358
Distraction osteogenesis; Mandible; Reconstruction; Transport
12.  Reconstruction of mandibular defects - clinical retrospective research over a 10-year period - 
Head & Neck Oncology  2011;3:23.
Functional and cosmetic defects in the maxillofacial region are caused by various ailments and these defects are addressed according to their need. Simplicity of procedure, intact facial function and esthetic outcome with the least possible donor site morbidity are the minimum requirements of a good reconstruction. Oro-mandibular reconstruction, although a challenge for the head and neck reconstructive surgeon, is now reliable and highly successful with excellent long-term functional and aesthetic outcomes with the use of autogenous bone grafts. Reconstruction of trauma- or mandibular oncologic defects with bony free flaps is considered the gold standard. However the the optimal reconstruction of mandibular defects is still controversial in regards to reconstructive options which include the donor site selection and the timing of surgery. The purpose of this study was to determine the outcome of different osseous reconstruction options using autogenous bone grafts for mandibular reconstructions.
This study was carried out on 178 patients with mandibular bone defects. They were reconstructed with autogenous bone grafts from different donor sites. At post operative visits they were evaluated for functional and cosmetic results.
The success rate found in this study was around 90%. Only 7.6% of the cases showed poor results regarding facial contours and mouth opening. All other patients were satisfied with their cosmesis and mouth opening at the recipient sites was in the normal range during last follow-up visits. Donor sites were primarily closed in all cases and there was no hypertrophic scar.
Based on this study, autogenous bone grafts are a reliable treatment modality for the reconstruction of mandibular bone defects with predictable aesthetic and functional outcomes. As the free vascularized fibular flap has the least resorption and failure rate, it should be the first choice for most cases of mandiblular reconstruction.
PMCID: PMC3098818  PMID: 21527038
13.  Bifocal Distraction to Regenerate Segmental Mandibular Defects Using a Custom Made Device: A Report of Two Cases 
Background and objective: Mandibular reconstruction following tumor ablative surgery had been a challenge. It has gone through days of temporary stabilization with k-wire, stainless steel reconstruction plate to avascularized and vascularized bone grafts with varying degree of success and failure. Reconstruction with vascularized bone grafts, though most definitive, requires special expertise, expensive equipment, and long operative time. It also produces donor site morbidity and requires a significant learning curve. With the development of transport distraction techniques there has been a paradigm shift from “reconstructive” to “regenerative” surgery. The objective of this study was to identify the feasibility of an internal device for reconstruction of extensive mandibular defects. Methods and material: This article is to highlight a process of attempted mandibular regeneration in two cases using an indigenously designed distractor device. In individuals with extensive post ablative mandibular defects who were unwilling to have a secondary surgical site or were medically unfit for a long reconstructive procedure, the distraction technique can be used to reconstruct the lost mandibular structures. Conclusion: A satisfactory amount of regenerate was achieved using a bifocal distraction osteogenesis technique for extensive defects of the mandible. The custom made device which was used for this purpose was moderately satisfactory and requires further evaluation and refinement.
PMCID: PMC3052676  PMID: 22110823
Transport distraction; extensive mandibular defects; single unit distractor device; mandibular reconstruction
14.  Reconstruction of Mandibular Defects 
Seminars in Plastic Surgery  2010;24(2):188-197.
Defects requiring reconstruction in the mandible are commonly encountered and may result from resection of benign or malignant lesions, trauma, or osteoradionecrosis. Mandibular defects can be classified according to location and extent, as well as involvement of mucosa, skin, and tongue. Vascularized bone flaps, in general, provide the best functional and aesthetic outcome, with the fibula flap remaining the gold standard for mandible reconstruction. In this review, we discuss classification and approach to reconstruction of mandibular defects. We also elaborate upon four commonly used free osteocutaneous flaps, inclusive of fibula, iliac crest, scapula, and radial forearm. Finally, we discuss indications and use of osseointegrated implants as well as recent advances in mandibular reconstruction.
PMCID: PMC3324243  PMID: 22550439
Bone flap; condyle; fibular flap; mandible; osseointegrated implant; osteocutaneous flap
15.  Apatite-coated Silk Fibroin Scaffolds to Healing Mandibular Border Defects in Canines 
Bone  2009;45(3):517-527.
Tissue engineering has become a new approach for repairing bony defects. Highly porous osteoconductive scaffolds perform the important role for the success of bone regeneration. By biomimetic strategy, apatite-coated porous biomaterial based on silk fibroin scaffolds (SS) might provide an enhanced osteogenic environment for bone-related outcomes. To assess the effects of apatite-coated silk fibroin (mSS) biomaterials for bone healing as a tissue engineered bony scaffold, we explored a tissue engineered bony graft using mSS seeded with osteogenically induced autologous bone marrow stromal cells (bMSCs) to repair inferior mandibular border defects in a canine model. The results were compared with those treated with bMSCs/SS constructs, mSS alone, SS alone, autologous mandibular grafts and untreated blank defects. According to radiographic and histological examination, new bone formation was observed from 4 weeks post-operation, and the defect site was completely repaired after 12 months for the bMSCs/mSS group. In the bMSCs/SS group, new bone formation was observed with more residual silk scaffold remaining at the center of the defect compared with the bMSCs/mSS group. The engineered bone with bMSCs/mSS achieved satisfactory bone mineral densities (BMD) at 12 months post-operation close to those of normal mandible (p>0.05). The quantities of newly formed bone area for the bMSCs/mSS group was higher than the bMSCs/SS group (p<0.01), but no significant differences were found when compared with the autograft group (p>0.05). In contrast, bony defects remained in the center with undegraded silk fibroin scaffold and fibrous connective tissue, and new bone only formed at the periphery in the groups treated with mSS or SS alone. The results suggested apatite-coated silk fibroin scaffolds combined with bMSCs could be successfully used to repair mandibular critical size border defects and the premineralization of these porous silk fibroin protein scaffolds provided an increased osteoconductive environment for bMSCs to regenerate sufficient new bone tissue.
PMCID: PMC2828815  PMID: 19505603
Tissue engineering; Silk; Apatite; Bone marrow stromal cells; Canine
16.  Mandibular Repair in Rats with Premineralized Silk Scaffolds and BMP-2-modified bMSCs 
Biomaterials  2009;30(27):4522-4532.
Premineralized silk fibroin protein scaffolds (mSS) were prepared to combine the osteoconductive properties of biological apatite with aqueous-derived silk scaffold (SS) as a composite scaffold for bone regeneration. The aim of present study was to evaluate the effect of premineralized silk scaffolds combined with bone morphogenetic protein-2 (BMP-2) modified bone marrow stromal cells (bMSCs) to repair mandibular bony defects in a rat model. bMSCs were expanded and transduced with adenovirus AdBMP-2, AdLacZ gene in vitro. These genetically modified bMSCs were then combined with premineralized silk scaffolds to form tissue engineered bone. Mandibular repairs with AdBMP-2 transduced bMSCs/mSS constructs were compared with those treated with AdLacZ transduced bMSCs/mSS constructs, native (nontransduced) bMSCs/mSS constructs and mSS alone. Eight weeks post-operation, the mandibles were explanted and evaluated by radiographic observation, micro-CT, histological analysis and immunohistochemistry. The presence of BMP-2 gene enhanced tissue engineered bone in terms of the most new bone formed and the highest local bone mineral densities (BMD) found. These results demonstrated that premineralized silk scaffold could serve as a potential substrate for bMSCs to construct tissue engineered bone for mandibular bony defects. BMP-2 gene therapy and tissue engineering techniques could be used in mandibular repair and bone regeneration.
PMCID: PMC2871698  PMID: 19501905
17.  Pediatric Mandibular Resection and Reconstruction: Long-Term Results with Autogenous Rib Grafts 
Reconstruction of mandibular defects following tumor resection in infants is a particular challenge. Although autogenous rib grafts have no relevance in the restoration of mandibular bone defects occurring after ablative tumor surgery due to limited bone stock and the availability of other donor areas, they are a useful surgical alternative following tumor surgery in infants. We here report on a 2, 5, 8, and 15-year follow-up of four children who were diagnosed with benign tumors of the mandible with osseous destruction at the age of 4, 6, 15, and 18 months, respectively. Histologic diagnoses were melanotic neuroectodermal tumor (n = 2), hemangioendothelioma of the mandible (n = 1), and ameloblastoma (n = 1). Following continuity resection of the mandible, lateromandibular bone defects were restored using autogenous rib grafts. Both clinical and radiologic follow-up visits were performed for all children to assess growth of the facial skeleton and the mandible. One child was already further reconstructed using bone augmentation at the age of 15 years. Cephalometric measurements on panorex films and three-dimensional computed tomographic scans revealed a slight vertical growth excess and transversal growth inhibition of the reconstructed mandible compared with the nonoperated side. Although further growth of rib grafts is difficult to predict and occlusal disharmony may occur due to physiologic maxillary growth and growth of the unaffected mandible, we believe that autogenous rib grafts can be ideally used for the restoration of mandibular continuity defects in newborns and young children. Clinical follow-up visits on a yearly basis and orthodontic controls are useful for early orthodontic treatment of growth deficits. Further corrective surgery with bone augmentation or osseous distraction is required following completion of growth of the facial skeleton.
PMCID: PMC3052664  PMID: 22110815
Mandibular reconstruction; rib graft; facial growth; bone graft; pediatric maxillofacial tumor
18.  Biomechanical characteristics of regenerated cortical bone in the canine mandible 
To test the mechanical properties of regenerate cortical bone created using Mandibular Bone Transport (MBT) distraction, five adult male American foxhound dogs underwent unilateral distraction of the mandible with a novel MBT device placed to linearly repair a 30-35 mm bone defect. The animals were sacrificed 12 weeks after the beginning of the consolidation period. Fourteen cylindrical specimens were taken from the inner (lingual) and outer (buccal) plates of the reconstructed mandible and 21 control specimens were removed from the contralateral aspect of the mandible. The mechanical properties of the 35 cylindrical cortical bone specimens were assessed by using a non-destructive pulse ultrasound technique. Results showed that all of the cortical mechanical properties exhibit higher numerical values on the control side than the MBT regenerate side. In addition, both densities and the elastic moduli in the direction of maximum stiffness of the regenerate cortical bone specimens are higher on the lingual side than the buccal side. Interestingly, there is no statistical difference between elastic modulus (E1 and E2) in orthogonal directions throughout the 35 cortical specimens. The data suggest that the regenerate canine cortical bone is not only heterogeneous, but the elastic mechanical properties tend to approximate transverse isotropy at a tissue level as opposed to control cortical bone that is orthotropic. In addition, the elastic mechanical properties are not only higher on the control side but also in the lingual anatomical position, suggesting a stress shielding effect from the presence of the reconstruction plate.
PMCID: PMC3116951  PMID: 21695796
Ultrasound technique; animal model; bony tissue; bone transport; distraction device; bone healing; jaw mechanics
19.  Role of parathyroid hormone therapy in reversing radiation-induced nonunion and normalization of radiomorphometrics in a murine mandibular model of distraction osteogenesis 
Head & neck  2013;35(12):1732-1737.
The use of mandibular distraction osteogenesis (MDO) for tissue replacement after oncologic resection or for defects caused by osteoradionecrosis has been described but, in fact, has seen limited clinical utility. Previous laboratory work has shown that radiation (XRT) causes decreased union formation, decreased cellularity, and decreased mineral density in an animal model of MDO. Our global hypothesis is that radiation-induced bone damage is partly driven by the pathologic depletion of both the number and function of osteogenic cells. Parathyroid hormone (PTH) is a U.S. Food and Drug Administration-approved anabolic hormonal therapy that has demonstrated efficacy for increasing bone mineral density for the treatment of osteoporosis. We postulate that intermittent systemic administration of PTH will serve as an anabolic stimulant to cellular function that will act to reverse radiation-induced damage and enhance bone regeneration in a murine mandibular model of DO.
A total of 20 isogenic male Lewis rats were randomly assigned into 3 groups. Group 1 (XRT-DO, n = 7) and group 2 (XRT-DO-PTH, n = 5) received a human bioequivalent dose of 70 Gy fractionated over 5 days. All groups including group 3 (DO, n = 8) underwent a left unilateral mandibular osteotomy with bilateral external fixator placement. Four days later, mandibular DO was performed at a rate of 0.3 mm every 12 hours to reach a maximum gap of 5.1 mm. Group 2 was injected PTH (60 μg/kg) subcutaneously daily for 3 weeks following the start of MDO. On postoperative day 41, all left hemimandibles were harvested. Micro-CT at 45-μm voxel size was performed and radiomorphometrics parameters of bone mineralization were generated. Union quality was evaluated on a 4-point qualitative grading scale. Radiomorphometric data were analyzed using 1-way ANOVA, and union quality assessment was analyzed via the Mann–Whitney test. Statistical significance was considered at p ≤ .05.
Groups 1 and 2 appropriately demonstrated clinical signs of radiation-induced stress ranging from alopecia to mucositis. Union quality was significantly higher in PTH-treated XRT-DO animals, compared with XRT-DO group animals (p = .02). Mineralization metrics, including bone volume fraction (BVF) and bone mineral density (BMD), also showed statistically significant improvement. The groups that were treated with PTH showed no statistical differences in union or radiomorphometrics when compared with DO in nonradiated animals.
We have successfully demonstrated the therapeutic efficacy of PTH to stimulate and enhance bone regeneration in our irradiated murine mandibular model of DO. Our investigation effectively resulted in statistically significant increases in BMD, BVF, and clinical unions in PTH-treated mandibles. PTH demonstrates immense potential to treat clinical pathologies where remediation of bone regeneration is essential.
PMCID: PMC4160101  PMID: 23335324
parathyroid hormone; distraction osteogenesis; radiation; mandible; mineral density
20.  Stem Cells from Deciduous Tooth Repair Mandibular Defect in Swine 
Journal of dental research  2009;88(3):249-254.
Stem cells from human exfoliated deciduous teeth have been identified as a new post-natal stem cell population with multipotential differentiation capabilities, including regeneration of mineralized tissues in vivo. To examine the efficacy of utilizing these stem cells in regenerating orofacial bone defects, we isolated stem cells from miniature pig deciduous teeth and engrafted the critical-size bone defects generated in swine mandible models. Our results indicated that stem cells from miniature pig deciduous teeth, an autologous and easily accessible stem cell source, were able to engraft and regenerate bone to repair critical-size mandibular defects at 6 months post-surgical reconstruction. This pre-clinical study in a large-animal model, specifically swine, allows for testing of a stem cells/scaffold construct in the restoration of orofacial skeletal defects and provides rapid translation of stem-cell-based therapy in orofacial reconstruction in human clinical trials.
PMCID: PMC2829885  PMID: 19329459
deciduous tooth; stem cell; bone; tissue engineering; miniature pig
21.  Stem Cells from Deciduous Tooth Repair Mandibular Defect in Swine 
Journal of Dental Research  2009;88(3):249-254.
Stem cells from human exfoliated deciduous teeth have been identified as a new post-natal stem cell population with multipotential differentiation capabilities, including regeneration of mineralized tissues in vivo. To examine the efficacy of utilizing these stem cells in regenerating orofacial bone defects, we isolated stem cells from miniature pig deciduous teeth and engrafted the critical-size bone defects generated in swine mandible models. Our results indicated that stem cells from miniature pig deciduous teeth, an autologous and easily accessible stem cell source, were able to engraft and regenerate bone to repair critical-size mandibular defects at 6 months post-surgical reconstruction. This pre-clinical study in a large-animal model, specifically swine, allows for testing of a stem cells/scaffold construct in the restoration of orofacial skeletal defects and provides rapid translation of stem-cell-based therapy in orofacial reconstruction in human clinical trials.
PMCID: PMC2829885  PMID: 19329459
deciduous tooth; stem cell; bone; tissue engineering; miniature pig
22.  The accuracy of computer-assisted primary mandibular reconstruction with vascularized bone flaps: iliac crest bone flap versus osteomyocutaneous fibula flap 
The intention of mandibular reconstruction is to restore the complex anatomy with maximum possible functionality and high accuracy. The aim of this study was to evaluate the accuracy of computer-assisted surgery in primary mandibular reconstruction with an iliac crest bone flap compared with an osteomyocutaneous fibula flap.
Materials and methods
Preoperative computed tomography data of the mandible and the iliac crest or fibula donor site were imported into a specific surgical planning software program. Surgical guides were manufactured using a rapid prototyping technique for translating the virtual plan, including information on the transplant dimensions and shape, into real-time surgery. Using postoperative computed tomography scans and an automatic surface-comparison algorithm, the actual postoperative situation was compared with the preoperative virtual simulation.
The actual flap position showed a mean difference from the virtual plan of 2.43 mm (standard deviation [SD] ±1.26) and a surface deviation of 39% <2 mm and 15% <1 mm for the iliac crest bone flap, and a mean difference of 2.18 mm (SD ±1.93) and a surface deviation of 60% <2 mm and 37% <1 mm for the osteomyocutaneous fibula flap. The position of the neomandible reconstructed with an osteomyocutaneous fibula flap indicated a mean difference from the virtual plan of 1.25 mm (SD ±1.31) and a surface deviation of 82% <2 mm and 57% <1 mm, in contrast to a mean difference of 1.68 mm (SD ±1.25) and a surface deviation of 63% <2 mm and 38% <1 mm for the neomandible after reconstruction with an iliac crest bone flap. For shape analysis, a similarly high accuracy could be calculated for both flaps.
Virtual surgical planning is an effective method for mandibular reconstruction with vascularized bone flaps, and can help to restore the anatomy of the mandible with high accuracy in position and shape. It seems that primary mandibular reconstruction with the osteomyocutaneous fibula flap is more accurate compared with the vascularized iliac crest bone flap.
PMCID: PMC4064953  PMID: 24966700
computer-assisted surgery; virtual planning; vascularized bone flaps; surgical guide; primary mandibular reconstruction
23.  The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages 
Biomaterials  2013;34(38):9853-9862.
Endogenous signals originating at the site of injury are involved in the paracrine recruitment, proliferation, and differentiation of circulating progenitor and diverse inflammatory cell types. Here, we investigate a strategy to exploit endogenous cell recruitment mechanisms to regenerate injured bone by local targeting and activation of sphingosine-1-phosphate (S1P) receptors. A mandibular defect model was selected for evaluating regeneration of bone following trauma or congenital disease. The particular challenges of mandibular reconstruction are inherent in the complex anatomy and function of the bone given that the area is highly vascularized and in close proximity to muscle. Nanofibers composed of poly(DL-lactide-co-glycolide) (PLAGA) and polycaprolactone (PCL) were used to delivery FTY720, a targeted agonist of S1P receptors 1 and 3. In vitro culture of bone progenitor cells on drug loaded constructs significantly enhanced SDF1α mediated chemotaxis of bone marrow mononuclear cells. In vivo results show that local delivery of FTY720 from composite nanofibers enhanced blood vessel ingrowth and increased recruitment of M2 alternatively activated macrophages, leading to significant osseous tissue ingrowth into critical sized defects after 12 weeks of treatment. These results demonstrate that local activation of S1P receptors is a regenerative cue resulting in recruitment of wound healing or anti-inflammatory macrophages and bone healing. Use of such small molecule therapy can provide an alternative to biological factors for the clinical treatment of critical size craniofacial defects.
PMCID: PMC3797185  PMID: 24064148
Craniofacial Reconstruction; S1P; FTY720; Neovascularization; Bone Healing
24.  Use of Recombinant Bone Morphogenetic Protein 2 in Free Flap Reconstruction for Osteonecrosis of the Mandible 
Osteoradionecrosis of the mandible is a debilitating consequence of radiation therapy for head-and-neck malignancy. It can result in pain, bone exposure, fistula formation, and pathologic fracture. Recombinant human bone morphogenetic protein 2 (rhBMP-2) has shown promise in reconstruction of bone defects. The purpose of this study is to determine whether the addition of rhBMP-2 at the union of vascularized bone and native bone improves surgical outcomes in patients with osteonecrosis of the mandible.
Materials and Methods:
This study was a retrospective analysis of patients who were treated between 2006 and 2010 for osteonecrosis of the mandible. Patients requiring definitive reconstruction after failure of a course of conservative management were included. Patients were divided into 2 cohorts depending on whether rhBMP-2 was used during the reconstruction. The primary outcome measure was defined as stable mandibular union.
Seventeen patients were included. The development of malunion was similar in both groups (13% for rhBMP-2 group vs 11% for non–rhBMP-2 group). Infectious complications were similar between the groups (25% in rhBMP-2 group vs 56% in non–rhBMP-2 group, P = .33). The rates of hardware removal were similar for the 2 groups (33% in non–rhBMP-2 group vs 25% in rhBMP-2 group, P = .10). No cancer recurrences were observed in patients receiving rhBMP-2.
The use of rhBMP-2 is safe in free flap reconstruction of the mandible, but its ability to significantly improve patient outcomes, as measured by rates of malunion, reoperation, or infection, is still unknown.
PMCID: PMC3951353  PMID: 22177824
Oral oncology  2008;45(0):394-401.
Oral cancer is the sixth most common cancer worldwide, with a high prevalence in South Asia. Tobacco and alcohol consumption remain the most dominant etiologic factors, however HPV has been recently implicated in oral cancer. Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers. The factors that affect choice of treatment are related to the tumor and the patient. Primary site, location, size, proximity to bone, and depth of infiltration are factors which influence a particular surgical approach. Tumors that approach or involve the mandible require specific understanding of the mechanism of bone involvement. This facilitates the employment of mandible sparing approaches such as marginal mandibulectomy and mandibulotomy. Reconstruction of major surgical defects in the oral cavity requires use of a free flap. The radial forearm free flap provides excellent soft tissue and lining for soft tissue defects in the oral cavity. The fibula free flap remains the choice for mandibular reconstruction.
Over the course of the past thirty years there has been improvement in the overall survival of patients with oral carcinoma largely due to the improved understanding of the biology of local progression, early identification and treatment of metastatic lymph nodes in the neck, and employment of adjuvant postoperative radiotherapy and chemoradiotherapy.
The role of surgery in primary squamous cell carcinomas in other sites in the head and neck has evolved with integration of multidisciplinary treatment approaches employing chemotherapy and radiotherapy either sequentially or concurrently. Thus, larynx preservation with concurrent chemoradiotherapy has become the standard of care for locally advanced carcinomas of the larynx or pharynx requiring total laryngectomy. On the other hand, for early staged tumors of the larynx and pharynx, transoral laser microsurgery has become an effective means of local control of these lesions. Advances in skull base surgery have significantly improved the survivorship of patients with malignant tumors of the paranasal sinuses approaching or involving the skull base. Surgery thus remains the mainstay of management of a majority of neoplasms arising in the head and neck area. Similarly, the role of the surgeon is essential throughout the life history of a patient with a malignant neoplasm in the head and neck area, from initial diagnosis through definitive treatment, post-treatment surveillance, management of complications, rehabilitation of the sequelae of treatment, and finally for palliation of symptoms.
PMCID: PMC4130348  PMID: 18674952
Oral Cancer; Oral Cancer Surgery; Head and Neck Cancer; Head and Neck Cancer Surgery; Oral Cancer Outcomes; Multi-Modality Treatment; Advanced Mouth Cancer; Mouth Cancer Treatment; Multidisciplinary Treatment Oral Cancer

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