Faculty Bibliography

Background/Purpose: The aim of this study is to perform a cephalometric evaluation of the craniofacial skeleton of patients with TCS. Methods/Description: Retrospective single institution review of all patients (N= 104) with TCS and a preoperative cephalogram was conducted (30 patients). Patients were divided into three groups based on their ages: infancy (mean 0.62 yr; range:0.01-2.2 yrs) adolescence (mean 7.91 yr, range:5.18-11.26 yrs) and post adolescent-young adulthood (mean 17.04 yr; range:15.49-21.36 yrs). Right and left sides were evaluated separately if asymmetry was noted to be present (44 sides). The cephalometric variables were compared to Bolton and Moyers norms and also to each other using ANOVA and student's t-test. Results: All maxillary and mandibular measurements were significantly different from normative values with the exception of SNA and upper gonial angle (Na-Go-Me). SNB, SNPg angles were severely decreased and Pg (Pg-NB) was significantly retruded (p<0.001). Gonial angle (Ar-Go-Me) was significantly wider than normal as lower gonial angle (Ar-Go-Na) and antegonial angles were significantly increased (p<0.001) in all three age groups. There was no difference among the groups in terms of increased antegonial angles. All vertical plane angles (SN-MP, SN-GoGN, FH-MP, SN-PP, PP-MP) were increased significantly as well (p<0.001). Correspondingly, the ratio between lower anterior face height and total face height was significantly higher, while posterior face height to anterior face height was significantly decreased (p<0.001). More than half of the patients (N= 17/30) possessed a parasagittal symphyseal notch at the anterior surface of the chin. The depth and width of this notch were increased from infancy to adolescence (p<0.01). Accordingly, symphysis inclination (SN-Symp.) increased significantly over time (p<0.01). The maxillary posterior region showed decreased height (p<0.01). Our findings suggest that the maxillo-mandibular deformity demonstrates what we have termed a 'parasagittal orbito-maxillo-zygomatic cleft' which is aligned along the path of maximum mandibular atresia (diminished or missing coronoid, condylar processes and rami. Conclusions: When comparing cephalometric values in patients with TCS to Bolton and Moyers, all structures showed varying degrees of deformation or dislocation with the exception of maxillary sagittal position. These changes were most prevalent in the posterior maxillae, mandible, symphysis and antegonial area of the mandible. Certain skeletal changes did not show variance from infancy to adulthood, such as maxilla-mandibular angle and Wits value, however changes of the symphysis region became more severe over time. Further, soft tissue facial convexity increased severely in all growth periods

Background/Purpose: Autogenous ear reconstruction remains one of the most technically challenging procedures in plastic surgery. Current methods to autogenous ear construct design entail tracing the contralateral (unaffected) ear, if available, and using this 2 dimensional outline as a surgical model. This study explores the feasibility of creating in-house patient specific intraoperative 3D models of autogenous ear reconstruction. Methods/Description: A 3 dimensional photograph of the unaffected ear (3DMD, Atlanta, GA) of a patient with unilateral microtia was uploaded into Amira (FEI Company, Hillsboro, Oregon, USA) and transformed to a (.stl) digital model. After rendering the (.stl) model of the ear, it was imported into Blendere (Amsterdam, The Netherlands) where it was inverted along the vertical axis to create a working template of the contralateral ear. The depths of the scapha, triangular fossa and cymba were all deepened to accentuate these contours. Additional relief was added to the helical root to further define this structure. The final template was digitally separated to create the requisite auricular components for the Nagata technique reconstruction: helix; antihelical fold with the superior and inferior crus; base frame. The patient had an intact tragus. The helix was digitally straightened to optimize its use as a model. The complete auricular model and the separated auricular components were all individually 3D printed (Builder Premium 3D Printer, Noordwijkerhout, The Netherlands) using a polylactic acid filament and sterilized following the manufacturer's specifications (1218C for 1 hour and 30 minute dry cycle). Results: The total time of digital preparation was 5 hours. Total time of 3D printing was 5.5 hours. Total cost of manufacturing was $0.78. On the day of surgery these sterilized, patient-specific 3 dimensional models were brought to the operating room and placed on the back table with the ear sculpting tools and carving block. The sterilized models were placed on the cartilage grafts and the forms and relief of the cartilage construct was easily appreciated and incorporated into the cartilage shape. Compared to the classic auricular tracings also present during this surgery these 3D printed models contained more detailed anatomic information which eliminated much of the guesswork from auricular reconstruction and resulted in a more efficient and precise operation. Conclusions: Leveraging hardware, expertise and software platforms already existing within an academic medical center, affordable, sterilizable, patient-specific 3D auricular models can be manufactured and used during autogenous ear construction

Background/Purpose: Amniotic band sequence (ABS) is a complex congenital anomaly in which infants with no known genetic mutation have bands of maternal amniotic tissue wrapped around body parts, most commonly the limbs and digits. Two disparate theories attempt to explain the etiology of ABS. The extrinsic theory posits that disruption of the amnion is the primary event. The intrinsic theory suggests that the bands are the result of a fetal anomaly during development. Neither theory is widely accepted with proponents of both citing evidence to support their arguments. ABS is frequently associated with complex craniofacial clefting. We report a novel variation on this presentation, which strongly supports the intrinsic theory. Methods/Description: Three patients from two centers with complex craniofacial clefting and ABS were identified. The nature of the overlap of craniofacial clefting with banding phenotypes was characterized for each patient, with photographs, comprehensive physical exams, and Genetics evaluations. Results: The three patients presented with hypertelorism, plagioceph-aly, and different forms of complex craniofacial clefting: Patient 1-bilateral Tessier 2 with left Tessier 12 clefts, a left extrophic lacrimal duct and bilateral blindness, Patient 2-left Tessier 2 and right Tessier 3 clefts, Patient 3-right Tessier 12 cleft. Patient 1 had amniotic bands connecting the left extrophic lacrimal duct, left brow and left hand, with resultant complex acrosyndactyly. Patient 2 had partial amputations of the left 3rd-5th digits, and autotransplantation of 2 digits, with one along the ipsilateral Tessier 3 cleft and one on the parietal scalp, 2 cm above the left ear. Patient 3 had amputations of the 1st-4th digits of the right hand, and autotransplantation of a portion of an unspecified finger remnant onto the right brow. Conclusions: All three patients presented with amniotic bands connecting complex craniofacial clefts with ipsilateral digits, or amputated finger remnants reimplanted within ipsilateral clefts. This finding supports a model in which complex craniofacial clefts result in areas of exposed mesenchyme within the embryo. These exposed sticky areas are susceptible to adherence of ipsilateral fetal hands. In support of this possibility, facial and early digital development are temporally coincident, and these structures are anatomically adjacent early during embryogenesis. Exposed craniofacial mesenchyme also provides a surface for amniotic attachment, resulting in bands that lead to ABS, digital amputation and autotransplantation. An alternative extrinsic interpretation of this finding in which the amnion primarily ruptures is not supported, as this would have to occur around 8 weeks of embryonic development to cause the observed phenotypes. This is well before the amnion is likely to rupture from extrinsic forces. Therefore, these findings strongly suggest that development of amniotic bands occurs secondary to intrinsic fetal anomalies

Background/Purpose: The reconstruction of the wide Tessier #4 cleft is classically limited by persistent lower lid ectropion/medical canthal disruption or the incorporation of unaesthetically located scars which violate the subunit border principle of facial reconstruction. We present a novel repair technique which: can be applied at infancy; does not require tissue expansion; restores stable lower eyelid and medial canthal position; and respects the subunit border principle of facial repair. Methods/Description: A neonate with a complete, wide, Tessier #4 facial cleft presents with an over 2/3rd lower eyelid loss. Presurgical tape therapy was applied to lengthen the lateral tissues transversely and vertically. A Tenzel flap extended to a Schrudde cervicofacial flap was planned to radically mobilize the lower eyelid to the medial canthus in a tension-free manner. A robust vascular supply was maintained to this large flap using a deep plane dissection. Results: Surgical repair was performed at 3 months of age. No tissue expansion was used. A Tenzel pattern flap was mobilized in the subcutaneous plane. This flap was raised in continuity with a Schrudde cervicofacial flap raised in the deep plane. Facial nerves were directly visualized and preserved during the operation. A conjunctival flap was raised from the floor of the orbit was used to reconstruct the posterior lamella of the lower eyelid. The Tenzel/Schrudde flap was rotated, without tension over the defect and to the nose/cheek junction. At the time of inset, there was redundant flap skin superiorly at the level of the lower eyelid and medially at the area of the medial canthus. This redundancy was incorporated into the reconstruction to prevent ectropion and medial canthus disruption. Suspensory sutures were applied to the infraorbital rim and pyriform aperture to prevent sagging of the flap. A Millard repair was used to reconstruct the lip at the level of the philtrum. The flap demonstrated 100% take despite radical mobilization. The final scar followed the philtral line, the nasal/cheek junction, the subcilliary line and the anterior auricular/retro auricular border. Lower eyelid and medial canthal position was stable after 6 months. Facial nerve function was preserved with this approach. Conclusions: A Tenzel/Schrudde deep-plane cervicofacial flap can be safely applied to infants with a wide Tessier #4 facial cleft. No tissue expansion is needed. This is the first repair technique which places final scars perfectly along the subunit borders of the face while preserving lower eyelid and medial canthal position, even in the patient with significant lower eyelid loss

Organ development requires complex signaling by cells in different tissues. Epithelium and mesenchyme interactions are crucial for the development of skin, hair follicles, kidney, lungs, prostate, major glands, and teeth. Despite myriad literature on cell-cell interactions and ligand-receptor binding, the roles of extracellular vesicles in epithelium-mesenchyme interactions during organogenesis are poorly understood. Here, we discovered that approximately 100 nm exosomes were secreted by the epithelium and mesenchyme of a developing tooth organ and diffused through the basement membrane. Exosomes were entocytosed by epithelium or mesenchyme cells with preference by reciprocal cells rather than self-uptake. Exosomes reciprocally evoked cell differentiation and matrix synthesis: epithelium exosomes induce mesenchyme cells to produce dentin sialoprotein and undergo mineralization, whereas mesenchyme exosomes induce epithelium cells to produce basement membrane components, ameloblastin and amelogenenin. Attenuated exosomal secretion by Rab27a/b knockdown or GW4869 disrupted the basement membrane and reduced enamel and dentin production in organ culture and reduced matrix synthesis and the size of the cervical loop, which harbors epithelium stem cells, in Rab27aash/ash mutant mice. We then profiled exosomal constituents including miRNAs and peptides and further crossed all epithelium exosomal miRNAs with literature-known miRNA Wnt regulators. Epithelium exosome-derived miR135a activated Wnt/beta-catenin signaling and escalated mesenchymal production of dentin matrix proteins, partially reversible by Antago-miR135a attenuation. Our results suggest that exosomes may mediate epithelium-mesenchyme crosstalk in organ development, suggesting that these vesicles and/or the molecular contents they are transporting may be interventional targets for treatment of diseases or regeneration of tissues.

We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.

BACKGROUND: The increasing use of autologous fat grafting in breast cancer patients has raised concerns regarding its oncologic safety. This study evaluated patient outcomes and tumor recurrence following mastectomy reconstruction and autologous fat grafting. METHODS: Retrospective chart review identified patients who underwent mastectomy followed by breast reconstruction from 2010 to 2015. Eight hundred twenty-nine breasts met inclusion criteria: 248 (30.0 percent) underwent autologous fat grafting, whereas 581 (70.0 percent) breasts did not. Patient demographics, cancer characteristics, oncologic treatment, surgical treatment, surgical complications, local recurrence, and distant metastases were analyzed. RESULTS: Autologous fat grafting patients and control patients were of similar body mass index, smoking status, and BRCA status. Patients who underwent fat grafting were significantly younger than control patients and were less likely to have diabetes, hypertension, or hyperlipidemia. The two groups represented similar distributions of BRCA status, Oncotype scores, and hormone receptor status. Patients underwent one to four grafting procedures: one procedure in 83.1 percent, two procedures in 13.7 percent, three in 2.8 percent, and four in 0.4 percent. Mean follow-up time from initial surgery was 45.6 months in the fat grafting group and 38.8 months in controls. The overall complication rate following fat grafting was 9.4 percent. Among breasts undergoing surgery for therapeutic indications, there were similar rates of local recurrence (fat grafting group, 2.5 percent; controls, 1.9 percent; p = 0.747). Interestingly, mean time to recurrence was significantly longer in the fat grafting group (52.3 months versus 22.8 months from initial surgery; p = 0.016). CONCLUSIONS: Autologous fat grafting is a powerful tool in breast reconstruction. This large, single-institution study provides valuable evidence-based support for its oncologic safety. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

BACKGROUND: Composite grafts consisting of adipose tissue and skin have been reported in the literature but have been restricted to areas smaller than 4 to 5 cm. The senior author (D.T.W.C.) has developed a technique of adipose tissue-preserved full-thickness skin grafts for larger areas with success similar to that achieved with conventional full-thickness skin grafts. METHODS: All cases of the senior author involving a full-thickness skin graft were identified and reviewed to identify cases in which adipose tissue-preserved full-thickness skin grafts were used. Indication for skin grafting, anatomical location of recipient and donor sites, size of graft, total number of grafts received by each patient, and percentage take were extracted from patient charts. Graft take was measured between days 5 and 14. RESULTS: A total of 72 adipose tissue-preserved skin grafts on 47 patients were identified from 1994 to 2009, with a median follow-up of 8 years. The size of defect ranged from 0.7 to 210 cm, with a median area of 6 cm (interquartile range, 2.5 to 15 cm). Only six of 72 grafts were found to have less than 100 percent take. The lowest take percentage was 85 percent in a graft with an area of 2.6 cm. There were no graft failures. CONCLUSIONS: This study confirms the proof-of-concept that both larger and distant donor- site adipose tissue-preserved skin grafts are a viable alternative to conventional defatted full-thickness skin grafting. It appears that there is a low complication rate with respect to graft failure or incomplete graft take. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

BACKGROUND: The aim of this study is to identify cephalometric measurements associated with clinical severity in patients with Treacher Collins Syndrome (TCS). METHODS: A retrospective single-institutional review of patients with TCS was conducted. Pre-operative cephalograms and computed tomography scans (n=30) were evaluated. 50 cephalometric measurements were compared to age-specific normative data using ANOVA. These cephalometric measurements and the patient's Pruzansky classification were correlated to clinical severity using Spearman analysis. Clinical severity was defined as: severe (required tracheostomy), moderate (obstructive sleep apnea, oral cleft, or gastrostomy-tube), or mild (absence of listed co-morbidities). Cephalometric measurements with a strong correlation (rs>0.60) were identified as predictors of clinical severity. RESULTS: Cephalograms of the study population contained thirty measurements that were found to be significantly different from normative data (p<0.01). These measurements were largely related to maxillary/mandibular projection, maxillary/mandibular plane angle, mandibular morphology, facial height, facial convexity and mandible/throat position. Ten of these 30 statistically significant measurements in addition to Pruzansky classification were found to be strongly correlated (rs>.60) to clinical severity. These measurements include: Mandibular projection/position [Sella-Nasion-Pogonion (SN-Pg) rs=-0.64; Hyoid-Menton (Hy-Me) rs=-0.62]; Posterior facial height [Posterior Facial Height/Anterior Facial Height (PFH/AFH) rs=0.60; Condyle-Gonion (Co-Go) rs=-0.66]; Maxillary/mandibular plane angle [Sella-Nasion-Mandibular Plane (SN-MP) rs=0.62; Frankfort Horizontal-Mandibular Plane (FH-MP) rs=0.61; Sella-Nasion-Palatal Plane (SN-PP) rs=0.69; Sella-Nasion-Symphysis (SN-Symph) rs=-0.69; Pruzansky classification rs=0.82. CONCLUSIONS: Specific cephalometric measurements of increased mandibular retrognathia, decreased posterior facial height, more obtuse maxillary/mandibular plane angle and more obtuse symphasis notch angle are strongly correlated to increased clinical severity in patients with Treacher Collins syndrome.