Faculty Bibliography

BACKGROUND:Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. METHODS:Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 μm of dipyridamole (n = 6), 10,000 μm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. RESULTS:Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-μm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-μm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 μm versus 10,000 μm dipyridamole; p = 0.104), and rhBMP-2-coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 μm dipyridamole, and p = 0.938 versus 10,000 μm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. CONCLUSION/CONCLUSIONS:Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.

There are over 2 million long bone defects treated in the USA annually, of which ~5% will not heal without significant surgical intervention. While autogenous grafting is standard of care in simple defects, a customized scaffold for large defects in unlimited quantities is not available. Recently, a three-dimensionally (3D) printed bioactive ceramic (3DPBC) scaffold has been successfully utilized in the of repair critical sized long bone defects in vivo. In this study, 3DPBC scaffolds were augmented with Dipyridamole, an adenosine A2A receptor (A_2A R) indirect agonist, because of its known effect to enhance bone formation. Critical-sized full thickness segmental defects (~11mm x full thickness) defects were created in the radial diaphysis in New Zealand White rabbits (n=24). A customized 3DPBC scaffold composed of β-tricalcium phosphate was placed into the defect site. Groups included scaffolds that were collagen-coated (COLL), or immersed in 10μM, 100μM, or 1000μM Dipyridamole solution. Animals were euthanized 8 weeks post-operatively and the radii/ulna-scaffold complex retrieved, en bloc, for micro-CT, histological and mechanical analysis. Bone growth was assessed exclusively within scaffold pores and evaluated by microCT and advanced reconstruction software. Biomechanical properties were evaluated utilizing nanoindentation to assess the newly regenerated bone for elastic modulus (E) and hardness (H). MicroCT reconstructions illustrated bone in-growth throughout the scaffold, with an increase in bone volume dependent on the Dipyridamole dosage. Histological evaluation did not indicate any adverse immune response while revealing progressive remodeling of bone. These customized biologic 3DPBC scaffolds have the potential of repairing and regenerating bone. This article is protected by copyright. All rights reserved.

Objective: The purpose of this study was to assess the association between extent of brachial plexus injury and shoulder abduction/external rotation outcomes after spinal accessory nerve (SAN) to suprascapular nerve (SSN) transfer. Methods: A systematic review of the literature was conducted according to PRISMA guidelines. Inclusion criteria were studies reporting outcomes on patients undergoing SAN to SSN nerve transfer. Patients were excluded for the following reasons: age under 18, nerve transfer for reanimation of the shoulder other than SAN to SSN, and less than 12 months of follow-up postoperatively. Pooled analysis was performed, and primary outcomes were Medical Research Council (MRC) score and range of motion (ROM) for shoulder abduction and external rotation. Univariate logistic regression analysis was used to assess the association between extent of brachial plexus injury and shoulder abduction/external rotation outcomes after SAN to SSN transfer. A multivariate logistic regression analysis model including age, injury to surgery interval, and extent of injury as factors was also created. Results: Univariate logistic regression analysis showed greater extent of injury to be a predictor of poorer shoulder abduction outcomes (OR: 0.502; 95% CI: 0.260-0.971, p = 0.040). Multivariate logistic regression analysis confirmed this association (OR: 0.55; 95% CI: 0.236-0.877, p = 0.019). Extent of injury was not significantly associated with external rotation outcomes on univariate analysis (OR: 0.435; 95% CI: 0.095-1.995, p = 0.284) or multivariate analysis (OR: 0.445; 95% CI: 0.097-2.046, p = 0.298). Age and injury to surgery interval were not significantly associated with postoperative outcomes. Conclusions: More extensive brachial plexus injuries are associated with inferior outcomes after SAN to SSN transfer. A potential explanation for this finding includes lost contribution of muscles from the shoulder girdle that receive innervation from outside of the upper brachial plexus. The relationship between extent of injury and postoperative outcomes is important to recognize when determining and discussing operative intervention with patients.

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10^-8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10^-12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

INTRODUCTION/BACKGROUND:Ongoing combat operations in Iraq, Afghanistan, and other theaters have led to an increase in high energy craniomaxillofacial (CMF) wounds. These challenging injuries are typically associated with complex tissue deficiencies, evolving areas of necrosis, and bony comminution with bone and ballistic fragment sequestrum. Restoring form and function in these combat-sustained CMF injuries is challenging, and frequently requires local and distant tissue transfers. War injuries are different than the isolated trauma seen in the civilian sector. Donor sites are limited on patients with blast injuries and they may have preferences or functional reasons for the decisions to choose flaps from the available donor sites. METHODS:A case series of patients who sustained severe combat-related CMF injury and were treated at Walter Reed National Military Medical Center (WRNMMC) is presented. Our study was exempt from Institutional Review Board review, and appropriate written consent was obtained from all patients included in the study for the use of representative clinical images. RESULTS:Four patients treated by the CMF team at Walter Reed National Military Medical Center are presented. In this study, we highlight their surgical management by the CMF team at WRNMMC, detail their postoperative course, and illustrate the outcomes achieved using representative patient clinical images. We also supplement this case series demonstrating military approaches to complex CMF injuries with CMF reconstructive algorithms utilized by the senior author (EDR) in the management of civilian complex avulsive injuries of the upper, mid, and lower face are thoroughly reviewed. CONCLUSION/CONCLUSIONS:While the epidemiology and characteristics of military CMF injuries have been well described, their management remains poorly defined and creates an opportunity for reconstructive principles proven in the civilian sector to be applied in the care of severely wounded service members. The War on Terror marks the first time that microsurgery has been used extensively to reconstruct combat sustained wounds of the CMF region. Our manuscript reviews various options to reconstruct these devastating CMF injuries and emphasizes the need for steady communication between the civilian and military surgical communities to establish the best care for these complex patients.

Operative experience for the contemporary trainee has become exceedingly more challenging in the setting of more stringent hospital regulations. Surgical training is thus shifting toward more self-directed, independent learning to maximize operative opportunities as they become available; yet, this can prove difficult for complex surgeries like craniofacial procedures. The intricate anatomy and fine reconstructive techniques employed cannot be readily depicted onto a two-dimensional page. To address this educational gap, the Craniofacial Interactive Virtual Assistant-Pro Edition (CIVA-Pro) was developed as a web-based surgical simulator to aid learners with conceptualizing the surgical principles utilized in these cases. The current work reviews the Bilateral Sagittal Split Osteotomy module of CIVA-Pro, providing detailed narratives for each chapter with expert commentary on broadened indications and future directions.

INTRODUCTION/BACKGROUND:The number of patients who may benefit from evaluation for face transplantation in the United States (US) remains largely unknown. The goal of our study was to better delineate the pool of patients who might benefit from face transplant evaluation based on the characteristics and mechanisms of injury of previously reported face transplant recipients. METHODS:The authors utilized data from the National Electronic Injury Surveillance System-All Injury Program in this study. The US Census Bureau data were used for population estimates. Inclusion and exclusion criteria were determined based on the characteristics of face transplant recipients to date, and the mechanisms of injury they sustained ultimately necessitating face transplantation. Statistical significance was reached if P <0.05. RESULTS:The estimated annual incidence of preventable craniofacial injuries from firearms (44,266-58,299; 31.7% increase), burns (5712-19,433; 240.2% increase), and animal attacks (5355-14,666; 173.9% increase) increased from 2005 to 2014, whereas the estimated annual incidence of craniofacial injuries from machinery (3927-2933; 25.3% decrease) decreased between 2005 and 2014. The authors estimate the annual incidence rate to fall between 32.1 per 100,000 and 58.1 per 100,000 among individuals aged 20 to 64 in the US. CONCLUSION/CONCLUSIONS:In this study, the authors estimate the annual incidence rate of individuals aged 20 to 64 in the US who may benefit from face transplant evaluation and believe that this quantification has the potential to initiate actionable discussions regarding geographical and financial factors affecting access to care in this patient population.

INTRODUCTION/BACKGROUND:Online resources have become a major source of medical information for the general public. To date, there has not been an assessment of patient-oriented online resources for face and upper extremity transplantation candidates and patients. The goal of this study is to perform a comprehensive assessment of these resources. METHODS:Our analysis relied on 2 dimensions: comprehensiveness and readability. Comprehensiveness was evaluated using 14 predetermined variables. Readability was evaluated using 8 different readability scales through the Readability Studio Professional Edition Software (Oleander Software, Ltd, Vandalia, Ohio). Data were also collected from solid organ transplantation (SOT), specifically kidney and liver, programs for comparison. RESULTS:Face and upper extremity transplantation programs were significantly more likely to list exclusion criteria (73.9% vs 41.2%; P = 0.02), the need for life-long immunosuppression (87.0% vs 58.8%; P = 0.02), and benefits of transplantation (91.3% vs 61.8%; P = 0.01) compared with SOT programs. The average readability level of online resources by all face and upper extremity transplantation programs exceeded the sixth grade reading level recommended by the National Institutes of Health and the American Medical Association. The average reading grade level of online resources by these programs was also significantly higher than those of SOT with both exceeding the recommended reading level (13.95 ± 1.55 vs 12.60 ± 1.65; P = 0.003). CONCLUSIONS:Future efforts in face and upper extremity transplantation should be directed toward developing standardized, comprehensive, and intelligible resources with high-quality content and simple language.