Faculty Bibliography

This study investigates a comprehensive model of bone regeneration capacity of dypiridamole-loaded 3D-printed bioceramic (DIPY-3DPBC) scaffolds composed of 100% beta-tricalcium phosphate (β -TCP) in an immature rabbit model through the time of facial maturity. The efficacy of this construct was compared to autologous bone graft, the clinical standard of care in pediatric craniofacial reconstruction, with attention paid to volume of regenerated bone by 3D reconstruction, histologic and mechanical properties of regenerated bone, and long-term safety regarding potential craniofacial growth restriction. Additionally, long-term degradation of scaffold constructs was evaluated. At 24 weeks in vivo, DIPY-3DPBC scaffolds demonstrated volumetrically significant osteogenic regeneration of calvarial and alveolar defects comparable to autogenous bone graft with favorable biodegradation of the bioactive ceramic component in vivo. Characterization of regenerated bone reveals osteogenesis of organized, vascularized bone with histologic and mechanical characteristics comparable to native bone. Radiographic and histologic analyses were consistent with patent craniofacial sutures. Lastly, through application of 3D morphometric facial surface analysis, our results support that DIPY-3DPBC scaffolds do not cause premature closure of sutures and preserve normal craniofacial growth. Based on this novel evaluation model, this DIPY-3DPBC scaffold strategy is a promising candidate as a safe, efficacious pediatric bone tissue engineering strategy.

BACKGROUND:There is no quantitative evidence supporting one unilateral cleft lip (UCL) repair technique over the other with regard to scarring. We sought to evaluate the difference between the extended Mohler and Millard techniques, using 3 scar assessment scales. METHODS:Postoperative frontal and basal photographs of patients undergoing UCL repair were reviewed. Three validated scar assessment scales were used: the Manchester Scar Scale (MSS), modified scar-rating scale (MSRS), and Stony Brook Scar Evaluation Scale. Lip and nose scars were rated by 5 independent raters using each of the scales. Interrater reliability was assessed using the intraclass correlation coefficient (ICC). RESULTS:Assessment of 116 images for 58 consecutive patients undergoing UCL repair (36 extended Mohler, 22 Millard) was performed. Interrater reliability was excellent for lip scars (ICCs, 0.903 [0.857-0.938] for MSS, 0.913 [0.872-0.944] for MSRS, and 0.850 [0.775-0.902] for SBES) and moderate for nose scar assessment (ICCs, 0.714 [0.579-0.816] for MSS, 0.693 [0.548-0.802] for MSRS, and 0.565 [0.359-0.720] for SBES). No statistically significant difference was found between the extended Mohler and Millard repairs in mean lip scar scores (MSS, 6.983 ± 1.469 vs 6.772 ± 1.175, P = 0.571; MSRS, 5.433 ± 1.530 vs 5.481 ± 1.290, P = 0.902; SBES, 3.633 ± 0.977 vs 3.446 ± 0.995, P = 0.483) or nose scar scores (MSS, 5.644 ± 1.131 vs 5.491 ± 0.689, P = 0.523; MSRS, 4.233 ± 0.987 vs 3.991 ± 0.705, P = 0.320; SBES, 3.933 ± 0.750 vs 4.018 ± 0.486, P = 0.603). CONCLUSIONS:Using 3 validated scar assessment scales, no significant difference was found between the extended Mohler and Millard techniques in terms of lip or nose scars.

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is one of the most commonly used osteogenic agents in the craniofacial skeleton. This study reviews the safety and efficacy of rhBMP-2 as applied to craniofacial reconstruction and assesses the level of scientific evidence currently available.

BACKGROUND:The Extended Mohler cleft lip repair restores upper lip form using a columellar flap to fill the defect created by the downward rotation of Cupid's bow. The resulting columella incision is mentioned as a potential drawback. This study seeks to evaluate the morbidity of the resulting scar. MATERIALS AND METHODS/METHODS:This retrospective study enrolled 50 unilateral cleft lip patients treated using the Extended Mohler repair. 5 reviewers examined post-operative images. Three validated scar assessment scales were utilized: Manchester Scar Scale (MSS), Modified Scar-Rating Scale (MSRS), and Stony Brook Scar Evaluation Scale (SBSES). A scar score for the lip and columellar portion of each patient was determined. RESULTS:Three different scar scales demonstrated significantly better scar quality for the columellar portion of the scar compared to the lip portion. The average score for the lip and columella using the MSS was 7.0 ± 1.4 and 5.7 ± 1.1 (P <0.001). The average score for the lip and columella using the MSRS was 5.5 ± 1.4 and 4.3 ± 0.9 (P <0.001). The average score for the lip and columella using the SBSES was 3.5 ± 1.1 and 3.9 ± 0.7 (P = 0.014). The intraclass correlation coefficient for lip scar assessments was 0.901 (MSS), 0.91 (MSRS), and 0.873 (Stony Brook Evaluation Scale [SBES]). The intraclass correlation coefficient for columellar scar assessment was 0.786 (MSS), 0.761 (MSRS), and 0.726 (SBES). CONCLUSION/CONCLUSIONS:The Extended Mohler unilateral cleft lip columellar scar is of superior quality compared to the lip portion. This analysis ameliorates one of the major concerns regarding the Extended Mohler cleft lip repair.

Background/Purpose: Intraoral myomucosal flaps such as the facial artery myomucosal (FAMM) flap and the buccal flap can provide effective palatal lengthening for the management of velopharyngeal insufficiency (VPI). This surgical approach is not without limitations and can result in increased postoperative burden to the patient and caregiver and frequently involves a second anesthetic event for pedicle division and flap inset. We sought to analyze the postoperative speech and functional outcomes of patients undergoing such procedures at our institution. Methods/Description: A retrospective assessment of all patients undergoing intraoral myomucosal flaps by a single surgeon at a tertiary academic institution was conducted. Only patients undergoing bilateral FAMM or buccal flaps for VPI were included. Data included demographic characteristics, flap-related complications, and postoperative speech and oral function. Results were compared between 2 age groups (group 1: <13, group 2: >=13). Analysis was performed over 5 clinical time points: preoperatively (T0), and postoperatively at 1 to 4 weeks (T1), 3 to 6 months (T2), and 1 to 3 years (T3).
Result(s): Of 54 patients reviewed, 24 met inclusion criteria: fourteen (58.3%) underwent bilateral FAMM flaps and 10 (41.7%) buccal flaps. Group 1 included 15 (62.5%) patients (median age: 6; range: 4-12) and group 2 included 9 (37.5%; median age: 23; range: 13-52). Group 1 patients were more likely to undergo buccal (60%), whereas group 2 were more likely to undergo FAMM flaps (88.9%). No intraor postoperative donor site complications, bleeding, flap necrosis, or dehiscence were noted. Subsequent pedicle division was performed in 66.7% of patients in group 1 (median: 35 days, range: 18-174) and 55.6% in group 2 (median: 46 days, range: 35-980) for interference with mastication in 10 (41.7%) patients, timing with other elective procedures in 3 (12.5%), or molar eruption in 1 patient. Ten (41.7%) patients had longitudinal speech follow-up, 70% of which were from group 1. Structural hypernasality had completely resolved in 80% of patients at T1, and in the rest by T3. At T1, >50% displayed abnormal occlusion or tongue placement and weak articulatory contact, which subsequently resolved. Dysphagia, drooling, or reduced oral opening were noted at T1 in most patients but had largely resolved on follow-up.
Conclusion(s): FAMM and buccal flaps are effective palatal lengthening procedures with 100% resolution of structural hypernasality and minimal complications in our series. Patient age and timing of division of flap pedicles may have an effect on postoperative oral function. Our findings support the early division of FAMM and buccal flap pedicles

Background/Purpose: Our tissue engineering laboratory has previously demonstrated that dipyridamole-coated, 3D printed bioceramic (3DPBC) scaffolds comprised of B-tricalcium phosphate generate significantly more bone compared to negative controls in short-term growing animal model studies. No detrimental effects to the cranial suture were observed in any experimental animals. The longterm osteogenic efficacy and safety of our 3DPBC scaffold for tissue engineering in growing calvaria was assessed by describing bone regeneration compared to autogenous bone graft, scaffold degradation kinetics, and the effects of the construct on cranial growth over time. Methods/Description: Twenty-two 1-month-old (immature) New Zealand white rabbits underwent unilateral 11-mm craniotomy within 2 mm of the coronal and sagittal sutures. Rabbits' calvarial defects were repaired by 1 of 2 interventions: 3DPBC scaffolds coated with 1000 mM dipyridamole (n = 14) or autogenous calvarial bone graft (n = 8). Six rabbits from the 3DPBC scaffold group were sacrificed at 8 weeks. The remaining rabbits (n = 8 each group) were observed until craniofacial growth was completed (6 months) and then euthanized. Bone regeneration, scaffold degradation, and cranial suture patency were analyzed in Amira software using reconstructed microcomputed tomography (muCT) images. Cranial growth was assessed by comparing bilateral cephalometric measurements based on muCT images. Bone growth and suture patency were qualitatively evaluated through histologic analysis.
Result(s): After 6 months of healing, animals with defects repaired with 3DPBC scaffolds regenerated an average of 53.9% +/- 3.6% (mean +/- SEM) bone, compared to 53.5% +/- 3.6% in defects repaired with bone graft (P = .95). Unoperated calvarial bone porosity was 49.4%+/-2.0%. Scaffolds showed significant degradation at 6 months (15.1% +/-0.7%) compared to 8 weeks (23.2% +/- 0.9%; P<=.001). Comparative measurements of operated and unoperated sides showed no significant differences in asymmetry between scaffold and bone graft animals (P > .24). Analysis of histologic sections revealed well-vascularized, organized bone formation within scaffold interstices with no evidence of ectopic bone formation, excess inflammatory cells, or suture fusion.
Conclusion(s): Dipyridamole-coated 3D-printed bioceramic scaffolds bone regeneration is comparable to autogenous bone graft without showing signs of adverse events such as premature cranial suture fusion, or detrimental effects to facial growth. The scaffold demonstrates favorable absorption kinetics, highlighting the potential for this technology in pediatric bone tissue engineering

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