Faculty Bibliography

Background/Purpose: Informed decision-making in cleft care relies heavily on available information, including online resources. The American Medical Association (AMA) recommends that the readability of these resources does not exceed the sixth grade reading level. We evaluated the comprehensiveness and readability of patientoriented online resources provided by American Cleft Palate- Craniofacial Association (ACPA) Approved cleft lip and/or palate (CLP) Teams in the United States. Methods/Description: ACPA Approved CLP Team listings were reviewed between July 16, 2018, and July 30, 2018. Listings with nonfunctional website links prompted an Internet search for the corresponding websites. Teams with no accessible website or <30 sentences of content were excluded. Content comprehensiveness was scored by presence/absence of 20 variables derived from ACPA team approval standards. Content readability, defined as estimated reading grade level, was evaluated with 8 validated scales using a Professional Readability Software (Oleander Software, Ltd, Vandalia, Ohio). Readability was then compared to AMA recommendations. Linear regression was used to assess the relationship between comprehensiveness and readability.
Result(s): From 167 reviewed teams, 47 (28.1%) had nonfunctional links. After an Internet search, 17 (10.2%) had no accessible website, and 39 (23.4%) had <30 sentences. A total of 56 teams were thus excluded. The average comprehensiveness score for all 111 team websites included was 14.5 +/- 2.6 out of 20. The combined average reading level across all scales (10.7 +/- 1.9) exceeded the AMArecommended sixth grade reading level; this finding held true for each individual website. Children's Hospital-affiliated teams (n = 86) had a significantly higher comprehensiveness score (14.8 vs 13.5; P = .03) and better readability as evidenced by lower reading grade level (10.5 vs 11.4; P = .04). On linear regression, a higher comprehensiveness score significantly predicted better readability (beta = -0.226; P < .001; 95% CI: -0.359 to -0.092).
Conclusion(s): Online resources of ACPA Approved CLP Teams vary in accessibility and comprehensiveness, and exceed the recommended reading level. In order to better serve and educate patients with cleft lip and/or palate and their caregivers, future efforts should be directed toward developing standardized, comprehensive, accessible, and intelligible online resources, while ensuring validation of their content and language

Background/Purpose: Knowledge of cleft lip (CL) surgical markings is essential prior to performing the repair. Work hours restrictions, increased patient care documentation time, and requests by patients not to have trainees involved in their care are limiting the acquisition of this skill in the operating room. Textbooks provide 2-dimensional illustrations of CL markings; while the cost of 3-dimensional (3D) printed CL models prohibit their widespread utilization for this purpose. We propose 3D stone models as simple and affordable tools to teach surgical trainees unilateral CL markings. Methods/Description: Polyvinyl siloxane (PVS) impression material was used to create a negative of a patient with unilateral CL. Snapstone mixed with water was poured into the PVS impression to create unilateral CL stone models. Eleven plastic surgery residents were prospectively recruited in the study. They were provided with a textbook chapter and online module detailing surgical markings for unilateral CL repair, and were given 15 minutes of study time, before providing them with a unilateral CL stone model for performing the CL markings within 10 minutes. The participants were then provided with a standardized patient photograph for the same purpose. Learner satisfaction with the stone model and patient photograph as educational tools for learning surgical markings were evaluated using a modified survey based on the Student Evaluation of Educational Quality (SEEQ) survey, a validated tool for measuring higher education student satisfaction. Learner satisfactions with each tool were compared using a Mann-Whitney U test.
Result(s): The total production time of one stone model, including the PVS impression, was 10 minutes. The cost of one PVS impression and one stone model were 64 and 83 cents respectively, for a total of $1.47. Participants reported that when compared to the standardized patient photograph, the stone model was more stimulating (4.72 +/- 0.47 vs 3.82+/-0.87; U = 25.5; P = .01), increased their interest in the subject (4.63 +/- 0.50 vs 3.45 +/- 1.29; U = 26.5; P = .02), allowed better learning of the subject matter (4.54 +/- 0.52 vs 2.91 +/- 0.83; U = 5.0; P < .001), had greater clarity (4.64 +/- 0.50 vs 3.00 +/- 0.89; U = 6.0; P < .001), and was a more effective means of teaching CL markings (4.73 +/- 0.47 vs 2.91 +/- 1.04; U = 6.0; P < .001). Participants were also more likely to recommend the stone model (4.82+/-0.40) over the standardized patient photograph (3.00 +/- 1.10; U = 5.0; P < .001).
Conclusion(s): 3D stone models of the unilateral cleft lip deformity are affordable and simple to produce. Plastic surgery residents report that these models are superior training tools to learn cleft lip markings compared to patient photographs. These educational tools have the potential to overcome significant financial, logistic, and time constraints in teaching cleft lip surgery markings

Background/Purpose: Previous in vivo and in vitro animal studies demonstrate that the adenosine A2A receptor (A2AR) agonist dipyridamole (DIPY) stimulates robust osteogenic differentiation and proliferation without adverse effects on craniofacial suture development. However, no studies to date have been performed on human tissue. This study compares the effects of DIPY, BMP-2, and standard osteogenic media on osteogenic differentiation by human mesenchymal stem cells to lay the foundation for translating this bone tissue engineering approach to pediatric craniofacial reconstruction. Methods/Description: Pediatric mesenchymal stem cells were isolated from surplus bone taken from consented patients undergoing craniofacial surgery. Cells were cultured at early passage for 3 weeks in 1 of 7 experimental conditions: control media; osteogenic media (control + 100 muM beta-glycerophosphate, 0.1 muM dexamethasone and 100 mg/ mL L-ascorbic acid); osteogenic media + 200 ng/mL BMP-2; osteogenic media + 10, 100, 1000, or 10 000 muM DIPY. All experiments were performed in biological triplicates. Samples were analyzed using Alkaline phosphatase (ALP) assay at 6 hours, 24 hours, 48 hours, and 7 days as a marker of early osteogenic differentiation. At the end of the 3-week differentiation period, cells underwent immunocytochemistry to verify phalloidin, osteocalcin, and collagen I expression. Alizarin red staining was used to detect mineralization. Statistical analysis used 1-way ANOVA with Tukeys post hoc correction and multiple t test comparison of means.
Result(s): In all osteogenic conditions, relative peak ALP activity occurred at 48 hours. One thousand micrometer DIPY showed significantly increased peak ALP activity compared to BMP-2 (3.6 +/- 0.1 fold increase vs 3.1 +/- 0.1; P = .006). There was no significant difference between 1000 muM DIPY and osteogenic media (4.1 +/- 0.1; P = .36). At 3 weeks, immunocytochemistry revealed differentiation in all osteogenic conditions compared to control. One thousand micrometer DIPY cells showed greater evidence of mature osteogenic differentiation including cuboidal cell morphology and deposition of collagen I in an extracellular fibrillar network pattern compared to both control osteogenic media and BMP-2. Alizarin red quantification demonstrated significantly increased extracellular matrix mineralization at 100 muM(2.4+/-0.4; P = .002), 1000 muM (4.3+/-0.6; P = .001), and 10 000 muM (5.1 +/- 0.2; P < .0001) DIPY compared to nonosteogenic control medium (1.0 +/- 0.1). Matrix mineralization was not significantly different between BMP-2 (2.4 +/- 0.2) and 1000 muM DIPY (P = .08). ImageJ analysis revealed increased proportion of osteocalcin expressing cells (40.0% +/- 2.8%) in stem cells treated with 1000 muM of dipyridamole compared to control (1.0% +/- 0.6%), osteogenic (5.8% +/- 1.0%), and BMP-2 (16.9% +/- 2.2%; P < .0001).
Conclusion(s): Dipyridamole promotes early osteogenic differentiation and maturation of human bone-derived mesenchymal stem cells. These data suggest that dipyridamole may be an effective tissue engineering strategy for pediatric craniofacial reconstruction

Background/Purpose: Cleft deformities of the lip and palate affect nearly one in 500 to 700 births and lead to increased morbidity and mortality if untreated. Nevertheless, significant global disparities in access to timely and appropriate care still exist. The relatively basic infrastructure required to surgically correct these deformities and large unmet disease burden have resulted in a significant number of foundation-based cleft care initiatives focused toward developing countries. In this study, we evaluate the peer-reviewed literature generated by these foundations in an attempt to assess their clinical, scientific, educational, and economic impact. Methods/Description: A comprehensive review of the literature was performed using key search terms, and the level of evidence of identified articles was determined. Data were then analyzed to determine the different models of foundation-based cleft care in developing countries, as well as their clinical, scientific, educational, and economic impact.
Result(s): A total of 244 articles were identified through our search and reviewed. The levels of evidence of these articles were also determined, and included 3 (1.2%) level I, 62 (25.4%) level II, 11 (4.5%) level III, 59 (24.2%) level IV, 53 (21.7%) level V, and 56 (23.0%) articles that were not gradable. Foundation-based cleft care initiatives in developing countries have significantly contributed to a better understanding of disease epidemiology, barriers to care, safety considerations, complications and outcomes, as well as international and local cleft surgery education. The cleft care center model is more cost-effective than the surgical mission model and provides more sustainable care.
Conclusion(s): Foundation-based cleft care prevents significant morbidity in developing countries and has provided valuable resources for capacity building. The surgical mission model should be considered as a transitory conduit for establishing the more effective and sustainable cleft care center model of care

Background/Purpose: Despite the increasing trend toward ambulatory surgery rate in general, for cleft lip repair, 72.1% of patients in the United States are still hospitalized. Multiple centers have been studying this and with the very recent publishing of 2 large volume studies published in Plastic and Reconstructive Surgery supporting the safety of outpatient cleft lip surgery, it has become a high-profile debatable topic in cleft management. Last year at ACPA in the plastic surgery breakout session there was a heated debate on the topic between surgeons. And just this summer, one of the authors articles was featured as the PRS Journal Club article of the month via Social media, where there were 68 comments, 11 shares, and 40 likes, which placed the article in the TOP 15 most viewed article in PRS Journal's website. So this is a topic that more and more surgeons and craniofacial teams are thinking about and considering changing practice management but that deserves being brought into the spotlight to discuss all the pros and cons. The goal of the presentation are to present a literature review up to date on inpatient versus outpatient cleft lip surgery and have members of the panel share their and data behind their approach to postoperative cleft lip management. We would like to focus on what has been studied and reported versus what people practice because "that is how they were trained" or that is how they "historically" have always done it. Methods/Description: We will start with an overview of the literature surrounding inpatient versus outpatient cleft lip surgery and epidemiology about the numbers of institutions that do inpatients versus outpatient. If possible, we would like to include an audience poll to get an idea of practice patterns in the room. Then based on the recent published studies, each panelist will share different protocols that have been successful for outpatient cleft lip management and how that could be implemented if a center wants to consider outpatient cleft lip surgery. This includes: preoperative education that can be done by the team or nurse managers, perioperative management before, during, and after the operation, and postoperative care after they go home. All are very key components to a successful outpatient cleft lip management. We will also discuss the barriers to doing outpatient cleft lip surgery as well as having a panelist who consistently does inpatient cleft lip surgery to present the rationale behind their practice management and also their barriers to outpatient cleft lip surgery. I have reached out to a few people and will be discussing with them at the upcoming ASPS meeting to see who may be interested in joining the panel to discuss that. We will discuss the economic impact overall of practice changes to a predominantly outpatient surgery and also potential insurance policy impact. We think this will be a very useful topic for any team member participating in the care of a cleft lip patient

Background/Purpose: Alveolar cleft surgery is the most common bone reconstruction performed in patients with a cleft. Osteogenic agents such as BMP-2 have been used to restore the bony cleft without the morbidity of bone graft, but concerns remain regarding premature fusion of sutures, exuberant bone formation, and malignant degeneration. We have recently demonstrated that dipyridamole-coated, 3D printed bio-ceramic (3DPBC) scaffolds generate comparable bone amounts to BMP2 and significantly greater bone compared to negative controls in short-term growing animal model studies. No detrimental effects to growth sutures were noted in any animals. This study investigates the long-term osteogenic properties, degradation kinetics, and effects on facial growth of these tissue engineering constructs in growing animal models. Methods/Description: Twenty-two 1-month-old (immature) New Zealand white rabbits underwent creation of unilateral 3.5 x 3.5 mm alveolar defects. Each alveolar defect was repaired with either 3DPBC scaffolds coated with 1000 muM dipyridamole (n = 14) or with autogenous bone graft from the radius (n = 8). Six rabbits from the 3DPBC scaffold group were sacrificed at 8 weeks. The remaining rabbits (n = 8 each group) were euthanized following completion of craniofacial growth (6 months). Bone regeneration, scaffold degradation, and maxillary suture patency were calculated using CT images reconstructed and analyzed in Amira software. Facial symmetry was evaluated using dense-surface 3D modeling and validated with bilateral cephalometric measurements of maxillary projection. Bone growth and suture patency were qualitatively evaluated through histologic analysis.
Result(s): After 6 months, animals with defects repaired with 3DPBC scaffolds regenerated an average of 52.9% +/- 3.3% bone (mean +/- SEM), compared to 40.7%+/-4.0% in defects repaired with bone graft (P = .02). This is compared to unoperated alveolus occupied by 39.3% +/- 1.6% bone. Scaffolds showed significant degradation at 6 months (6.7% +/- 1.6%) compared to at 8 weeks (27.1% +/- 1.9%; P >= .001). Morphometric analysis using dense surface modeling showed similar symmetry indices of 55.0 +/- 3.3 for scaffold animals and 61.7% +/- 1.6% for bone graft animals (P = .10). Comparative measurements of operated and unoperated sides showed no significant differences in asymmetry between scaffold and bone graft animals (P = .86). Histologic analysis of scaffold samples revealed vascularized, organized bone within scaffold interstices without evidence of ectopic bone, excess inflammatory cells, or suture fusion.
Conclusion(s): In a growing animal model, dipyridamole-coated 3DPBC scaffolds can regenerate bone comparable to autogenous bone graft by radiographic and histologic analysis. Over 6 months, scaffolds show significant, favorable degradation and do not result in premature suture fusion or disruption of facial growth compared to bone graft. These results support long-term safety and efficacy of this tissue engineering strategy in the repair of alveolar cleft defects

OBJECTIVE/UNASSIGNED:Assess the weight and contribution of each of the parameters of the Asher-McDade Scale to overall subjective assessment of nasolabial aesthetics following cleft lip repair. DESIGN/UNASSIGNED:Retrospective cohort evaluation. SETTING/UNASSIGNED:Cleft and craniofacial center. PARTICIPANTS/UNASSIGNED:Forty-one patients who underwent unilateral cleft lip repair. INTERVENTIONS/UNASSIGNED:Unilateral cleft lip repair. MAIN OUTCOME MEASURES/UNASSIGNED:Nasolabial rating using the Asher-McDade scale and overall subjective assessment of nasolabial aesthetics using a rank score following unilateral cleft lip repair. RESULTS/UNASSIGNED:= .69; P < .001). CONCLUSION/UNASSIGNED:The parameters evaluated in the Asher-McDade scale have different weights and contribute differently to overall subjective assessment of nasolabial aesthetic outcomes following cleft lip repair. Adjusting for their weights results in a modified score that demonstrates superior correlation with overall subjective assessment of nasolabial aesthetic outcomes.

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.

BACKGROUND:Facial transplantation introduced a paradigm shift in the reconstruction of extensive facial defects. Although the feasibility of the procedure is well established, new challenges face the field in its second decade. METHODS:The authors' team has successfully treated patients with extensive thermal and ballistic facial injuries with allotransplantation. The authors further validate facial transplantation as a reconstructive solution for irreparable facial injuries. Following informed consent and institutional review board approval, a partial face and double jaw transplantation was performed in a 25-year-old man who sustained ballistic facial trauma. Extensive team preparations, thorough patient evaluation, preoperative diagnostic imaging, three-dimensional printing technology, intraoperative surgical navigation, and the use of dual induction immunosuppression contributed to the success of the procedure. RESULTS:The procedure was performed on January 5 and 6, 2018, and lasted nearly 25 hours. The patient underwent hyoid and genioglossus advancement for floor-of-mouth dehiscence, and palate wound dehiscence repair on postoperative day 11. Open reduction and internal fixation of left mandibular nonunion were performed on postoperative day 108. Nearly 1 year postoperatively, the patient demonstrates excellent aesthetic outcomes, intelligible speech, and is tolerating an oral diet. He remains free from acute rejection. CONCLUSIONS:The authors validate facial transplantation as the modern answer to the classic reconstructive challenge imposed by extensive facial defects resulting from ballistic injury. Relying on a multidisciplinary collaborative approach, coupled with innovative emerging technologies and immunosuppression protocols, can overcome significant challenges in facial transplantation and reinforce its position as the highest rung on the reconstructive ladder. CLINICAL QUESTION/LEVEL OF EVIDENCE/METHODS:Therapeutic, V.

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.