Repair of complex ovine segmental mandibulectomy utilizing customized tissue engineered bony flaps.

Craniofacial defects require a treatment approach that provides both robust tissues to withstand the forces of mastication and high geometric fidelity that allows restoration of facial architecture. When the surrounding soft tissue is compromised either through lack of quantity (insufficient soft tissue to enclose a graft) or quality (insufficient vascularity or inducible cells), a vascularized construct is needed for reconstruction. Tissue engineering using customized 3D printed bioreactors enables the generation of mechanically robust, vascularized bony tissues of the desired geometry. While this approach has been shown to be effective when utilized for reconstruction of non-load bearing ovine angular defects and partial segmental defects, the two-stage approach to mandibular reconstruction requires testing in a large, load-bearing defect. In this study, 5 sheep underwent bioreactor implantation and the creation of a load-bearing mandibular defect. Two bioreactor geometries were tested: a larger complex bioreactor with a central groove, and a smaller rectangular bioreactor that were filled with a mix of xenograft and autograft (initial bone volume/total volume BV/TV of 31.8 ± 1.6%). At transfer, the tissues generated within large and small bioreactors were composed of a mix of lamellar and woven bone and had BV/TV of 55.3 ± 2.6% and 59.2 ± 6.3%, respectively. After transfer of the large bioreactors to the mandibular defect, the bioreactor tissues continued to remodel, reaching a final BV/TV of 64.5 ± 6.2%. Despite recalcitrant infections, viable osteoblasts were seen within the transferred tissues to the mandibular site at the end of the study, suggesting that a vascularized customized bony flap is a potentially effective reconstructive strategy when combined with an optimal stabilization strategy and local antibiotic delivery prior to development of a deep-seated infection.

Osteoradionecrosis of the cervical spine: an analysis of the literature.

OBJECTIVES: The purpose of this manuscript is to review the current literature on osteoradionecrosis of the cervical spine (C-ORN) and to summarize the risk factors, presenting symptoms and management strategies of this rare condition. STUDY DESIGN: A systematic review of the literature on C-ORN was completed using PubMed. Nineteen articles met criteria; 97 patient cases were identified. Statistical analysis was completed from the patient cases. RESULTS: Of the analyzed patients, 72% are male and 28% are female with an average age of 57.7 years. Nasopharyngeal carcinoma was the most common initial diagnosis (72%). Thyroid and other lower neck cancers were associated with a later onset of C-ORN compared with other cancers. C-ORN more commonly occurred in the clivus to C2 (55.3%, P = .004). Onset of C-ORN significantly differed for men (n = 6.99 years) and women (n = 17.5 years) (P = .022). CONCLUSION: C-ORN can be a devastating complication of head and neck radiation therapy. C-ORN is associated with nasopharyngeal carcinoma, and most commonly affects the area of the clivus to cervical vertebrae C2. Cancers of the lower neck and female sex are associated with later onset. Initial presentation ranges from asymptomatic to severe neurologic deficits; the degree of intervention should be congruent with the severity of presenting symptoms. As long-term survival of patients with head and neck cancer increase, this complication may become more prevalent.

Fellowship Training in Oral and Maxillofacial Surgery: Opportunities and Outcomes.

The pursuit of fellowship training stems from one's desire to master a focused area of surgery. Successful applicants tend to have published articles and participated in other scholarly activities. They commonly have a mentor within the subspecialty of their interest. Selection of the program is generally based on the breadth of experience available followed by faculty reputation and location. Advantages to the successful fellowship graduate include the experience and confidence to provide specialized and efficient care to patients. Enhancements to an academic department with a fellowship program include mentorship for residents and guidance toward fellowship, as well as an increased level of scholarly activity.

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

A Combined Transoral and Contralateral Submandibular Approach in the Surgical Management of Osteoradionecrosis of the Mandible With Free Flap Reconstruction.

We describe a method for performing mandibular resection and vascularized tissue transfer via an intraoral and contralateral submandibular approach to minimize the risk of wound complications in a radiated field. Surgery on radiated tissue associated with osteoradionecrosis of the mandible can present with oral cutaneous fistulas, dense fibrotic skin, and altered tissue planes to make dissection through this tissue tedious and can place the marginal mandibular nerve at increased risk of injury. The use of custom plates allows surgeons to minimize incisions and depend less on anatomic/visual cues during surgery to obtain an accurate result. Our experience in 8 patients has shown a predictable method for resection and reconstruction of the mandible, while minimizing the potential complications associated with previously radiated and operated patients.

Brush swab as a noninvasive surrogate for tissue biopsies in epigenomic profiling of oral cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. METHODS: Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e., cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. RESULTS: There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation (r = 0.913 for cancer samples and r = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p-value = 0.00021) but not different between tissues and brush swabs (mean p-value = 0.11). CONCLUSIONS: Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

Localized mandibular infection affects remote in vivo bioreactor bone generation.

Mandibular reconstruction requires functional and aesthetic repair and is further complicated by contamination from oral and skin flora. Antibiotic-releasing porous space maintainers have been developed for the local release of vancomycin and to promote soft tissue attachment. In this study, mandibular defects in six sheep were inoculated with 106 colony forming units of Staphylococcus aureus; three sheep were implanted with unloaded porous space maintainers and three sheep were implanted with vancomycin-loaded space maintainers within the defect site. During the same surgery, 3D-printed in vivo bioreactors containing autograft or xenograft were implanted adjacent to rib periosteum. After 9 weeks, animals were euthanized, and tissues were analyzed. Antibiotic-loaded space maintainers were able to prevent dehiscence of soft tissue overlying the space maintainer, reduce local inflammatory cells, eliminate the persistence of pathogens, and prevent the increase in mandibular size compared to unloaded space maintainers in this sheep model. Animals with an untreated mandibular infection formed bony tissues with greater density and maturity within the distal bioreactors. Additionally, tissues grown in autograft-filled bioreactors had higher compressive moduli and higher maximum screw pull-out forces than xenograft-filled bioreactors. In summary, we demonstrated that antibiotic-releasing space maintainers are an innovative approach to preserve a robust soft tissue pocket while clearing infection, and that local infections can increase local and remote bone growth.

Virtual Surgical Planning in Oral and Maxillofacial Surgery.

Virtual surgical planning provides the ability to visualize the patient anatomy and pathologic condition, establish pertinent reference points, and simulate osteotomies and reconstruction design in advance of the surgery. Virtual surgical planning is also an ideal environment for improved communication between the patient and the surgical team.

Preparation of the Neck for Advanced Flap Reconstruction.

Microvascular free tissue transfer has revolutionized the reconstruction of complex maxillofacial defects. These cases often necessitate a 2-teamed approach, with an ablative surgeon at the head and a reconstructive surgeon at a distant site for flap harvest. Careful attention to recipient vessel identification and preservation establishes the foundation for successful reconstruction. This article describes the surgical landmarks of the frequently utilized arteries and veins, vessel handling techniques, and general principles for the preparation of free tissue transfer recipient sites in head and neck reconstruction.

Biomaterials-aided mandibular reconstruction using in vivo bioreactors.

Large mandibular defects are clinically challenging to reconstruct due to the complex anatomy of the jaw and the limited availability of appropriate tissue for repair. We envision leveraging current advances in fabrication and biomaterials to create implantable devices that generate bone within the patients themselves suitable for their own specific anatomical pathology. The in vivo bioreactor strategy facilitates the generation of large autologous vascularized bony tissue of customized geometry without the addition of exogenous growth factors or cells. To translate this technology, we investigated its success in reconstructing a mandibular defect of physiologically relevant size in sheep. We fabricated and implanted 3D-printed in vivo bioreactors against rib periosteum and utilized biomaterial-based space maintenance to preserve the native anatomical mandibular structure in the defect site before reconstruction. Nine weeks after bioreactor implantation, the ovine mandibles were repaired with the autologous bony tissue generated from the in vivo bioreactors. We evaluated tissues generated in bioreactors by radiographic, histological, mechanical, and biomolecular assays and repaired mandibles by radiographic and histological assays. Biomaterial-aided mandibular reconstruction was successful in a large superior marginal defect in five of six (83%) sheep. Given that these studies utilized clinically available biomaterials, such as bone cement and ceramic particles, this strategy is designed for rapid human translation to improve outcomes in patients with large mandibular defects.

Single-Unit 3D-Printed Titanium Reconstruction Plate for Maxillary Reconstruction: The Evolution of Surgical Reconstruction for Maxillary Defects-A Case Report and Review of Current Techniques.

The complex 3-dimensional anatomy of the facial skeleton creates a unique challenge for surgical reconstruction. Even more difficult is the precise reconstruction of the maxilla owing to its lack of solid bony support after large resections. Virtual surgical planning (VSP) technology has many applications in head and neck surgery, such as preoperative planning, fabrication of cutting guides and stereolithographic models, and fabrication of custom implants. We present the case of a patient who had undergone surgical resection of a mucoepidermoid carcinoma of the maxilla and immediate reconstruction with a vascularized free fibula flap using VSP. Using a custom 3-dimensional, titanium printed plate, which corresponded precisely with the surgical defect, the maxilla and midface were reconstructed to ideal dimensions with no unplanned surgical manipulation and a shorter overall operating time. We have described the technique and reviewed the pertinent reported data.

The Use of Acellular Urinary Bladder Matrix as Coverage for Fasciocutaneous Free Flap Donor Sites: An Alternative to Traditional Grafting Procedures.

PURPOSE: The purpose of this review is to 1) evaluate our early experience with urinary bladder matrix as a dressing for the management of complex wounds subsequent to fasciocutaneous or osteocutaneous vascularized tissue harvests, 2) assess coverage of exposed tendons and the duration of granulation and epithelial coverage, and 3) assess esthetic and functional outcomes compared with traditional means for the management of vascularized tissue harvest sites. PATIENTS AND METHODS: This prospective study consisted of 8 consecutive patients in whom a substantial cutaneous component was harvested as part of a vascularized tissue reconstruction, which did not permit for primary closure (n = 7) or had skin graft failure (exposed tendon) that required additional treatment (n = 1). RESULTS: Functional and esthetic outcomes were comparable to those of traditional methods of donor site closure as determined by clinical evaluation and subjective assessment by the patient. In all patients, no additional grafting was required to achieve full coverage. Irregularities of the wound achieved a level plane with granulation tissue an average of 3 to 4 weeks after surgery, followed by an additional 5 to 8 weeks for epithelialization. Wound care was minimal and included twice-daily wet-to-dry dressings. It was noted that complete wound healing was delayed in the urinary bladder matrix group, which required more attention during wound care when compared with published data. Advantages included facilitation of a robust granulation layer that leveled wound irregularities and avoidance of an additional skin graft site. CONCLUSIONS: The use of urinary bladder matrix is a viable option for the rehabilitation of donor sites of vascularized tissue that include skin. Benefits include the avoidance of an additional skin graft donor site, facilitation of epithelialization over exposed tendons, leveling of the donor site texture, and an equivalent esthetic result compared with current practices for wound coverage. The success of this technique may be limited by the cost of materials and the protracted course for wound epithelialization.

Tissue Engineered Prevascularized Bone and Soft Tissue Flaps.

The complex shapes of skeletal components of the craniofacial region combined with the prominence of the face and paucity of overlying soft tissue create significant challenges for the reconstructive surgeon. The in vivo bioreactor strategy is a promising alternative to microvascular surgical techniques that combines tissue engineering principles with microvascular reconstructive techniques to create patient-specific, prevascularized bone flaps for reconstruction of complex maxillofacial defects. This article discusses the use of traditional vascularized bone flaps; preclinical studies using the in vivo bioreactor approach; case reports that have attempted this novel technique; and future challenges and considerations in the development of patient-specific, prevascularized bone flaps for maxillofacial reconstruction.

Resection of an ameloblastoma in a pediatric patient and immediate reconstruction using a combination of tissue engineering and costochondral rib graft: A case report.

BACKGROUND AND OVERVIEW: Ameloblastoma is an odontogenic tumor predominantly occurring in patients who are in their 20s and 30s. Approximately 10% to 15% of ameloblastomas occur in patients younger than 18 years. Although it is a benign tumor, an ameloblastoma can have a devastating effect on children both physically and emotionally. The aim of this case report is to demonstrate how tissue engineering and surgical techniques can minimize morbidity and recovery time after extirpation and immediate reconstruction of a mandibular ameloblastoma. CASE DESCRIPTION: An 11-year-old girl was referred for surgical evaluation of a lesion found on a routine dental radiograph. Resection of a mandibular unicystic ameloblastoma resulted, including immediate reconstruction using a costochondral rib graft, allogeneic bone, bone marrow aspirate concentrate, and recombinant human morphogenetic protein-2. One year postoperatively, the patient had no evidence of recurrence as well as excellent mandibular bone height and width with good facial form. The patient has returned to her daily life without any disabilities or disfigurement. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Dentists are typically the first health care providers to discover oral pathology in patients. The coordination of care by the dental care providers and the oral and maxillofacial specialist was key to the successful outcome for this patient. With biotechnology and surgical techniques, the dental surgeon can extirpate an ameloblastoma and reconstruct the mandible defect to the ideal shape and size with minimal morbidity and recovery time.

Immediate Transoral Allogeneic Bone Grafting for Large Mandibular Defects. Less Morbidity, More Bone. A Paradigm in Benign Tumor Mandibular Reconstruction?

PURPOSE: Reconstruction of hard tissue continuity defects caused by ablative tumor surgery has been traditionally reconstructed with autogenous bone grafts or microvascular free flaps. Although results have been predictable from these 2 methods of reconstruction, the morbidity associated with bone harvest is quite serious for the patient. Predictable results have been obtained with using a combination of 100% cadaver bone, bone marrow aspirate concentrate (BMAC), and recombinant human bone morphogenic protein in immediate reconstruction for benign tumor extirpations through the extraoral approach. In light of these successful outcomes, the same combination was evaluated with an intraoral approach. This study evaluated the success of immediate mandibular reconstruction through the intraoral approach without any autogenous bone harvesting. PATIENTS AND METHODS: The aim of this retrospective study was to share the authors' experience with the use of 100% allogeneic bone in combination with bone morphogenic protein and BMAC through the transoral approach for immediate reconstruction of continuity defects that resulted from benign tumor surgery. A retrospective chart review was performed of all patients undergoing bone graft reconstruction at the University of Texas Health Sciences Center at Houston (UTHealth) Department of Oral and Maxillofacial Surgery from December 2014 through January 2016. Inclusion criteria were biopsy-proven benign tumors, American Society of Anesthesiologists I or II health status, and adequate intraoral soft tissue for primary closure determined during initial consultation. RESULTS: Five patients who underwent this procedure at the UTHealth Department of Oral and Maxillofacial Surgery from December 2014 through January 2016 are presented. The success rate was 100%. All patients showed excellent bone quality clinically and radiographically for endosseous dental implant placement. With the transoral approach and no autogenous bone harvesting, the average operating time was 3.4 hours and the hospital stay was 2.4 days. CONCLUSIONS: Composite allogeneic tissue engineering is an effective and predictable technique for immediate reconstruction of continuity defects from ablative benign tumor surgery. Overall, there was no donor site morbidity, the intraoperative time was shorter, there were fewer admission days, and total costs overall were lower compared with traditional methods.