Short-term Satisfaction, Psychosocial Impact, and Complication Profile of Reduction Mammaplasty During Adolescence.

BACKGROUND: Reduction mammaplasty is an effective and safe treatment option for adults with symptomatic macromastia, but there are few data regarding outcomes in adolescents. OBJECTIVES: The purpose of this study was to determine the short-term psychosocial impact, satisfaction, and safety of reduction mammaplasty when performed during adolescence. METHODS: A retrospective review was performed of a single pediatric plastic surgeon's experience with reduction mammaplasty from 2018 to 2021 in patients aged ≤18 years. Patients completed the preoperative and postoperative "Satisfaction with Breasts" and "Psychosocial Well-being" sections of the BREAST-Q survey. Clinical variables gathered included age, weight, BMI, complication profile, specimen resection weight, and follow-up duration. RESULTS: In total, 41 patients met inclusion criteria. The mean converted Rasch scores for BREAST-Q "Satisfaction with Breasts" and "Psychosocial Well-being" increased significantly following reduction mammaplasty ("Satisfaction with Breasts": preoperative, 24.1 vs postoperative, 92.6; "Psychosocial Well-being": preoperative, 37.7 vs postoperative, 90.4; P < .001). Obesity (BMI ≥ 30 kg/m2) was associated with lower preoperative "Psychosocial Well-being" scores (obese, 29.7 vs nonobese, 43.3; P < .001) but a greater improvement in score following surgery (obese, +63.9 vs nonobese, +44.9; P < .001). Specimen weight ≥1000 grams was also associated with greater improvement in score on the "Psychosocial Well-being" section (≥1000 grams, +58 vs <1000 grams, +49.7; P = .046). Overall complication rate was 31.7% while the major complication rate was 2.4%. Mean specimen resection weight was higher in patients who experienced complications (1141.3 grams vs 836.8 grams, P = .008). CONCLUSIONS: Reduction mammaplasty during adolescence predictably improves both short-term satisfaction with breasts and psychosocial well-being while demonstrating a favorable short-term complication profile.

Mandibular Distraction in Neonatal Pierre Robin Sequence: Is Immediate Extubation Both Feasible and Safe?

BACKGROUND: The timing of extubation following placement of mandibular distractors in the setting of Pierre Robin sequence is variable across institutional algorithms. Postoperative maintenance of intubation allows for an improvement in airway dimension and tongue positioning before extubation, theoretically decreasing the impact of postoperative airway edema. Maintenance of intubation, however, is not without risk. The authors analyze their institutional experience with neonatal mandibular distraction followed by immediate extubation to assess feasibility and safety profiles. METHODS: A 4-year retrospective review of patients diagnosed with Pierre Robin sequence who underwent mandibular distraction within the first 3 months of life was performed. Patients intubated preoperatively were excluded. RESULTS: Fifty-two patients met inclusion criteria. Thirty-eight patients (73 percent) were extubated immediately, whereas 14 patients (27 percent) remained intubated. No differences between these groups were found when comorbidities, cleft pathology, preoperative respiratory support, or grade of view on direct laryngoscopy were analyzed. Case duration greater than 120 minutes, operation start time after 3 pm, and the subjective designation of a difficult airway by the anesthesiologist were associated with maintaining intubation (p < 0.05). Eight patients (21 percent) in the extubated group required an increase in respiratory support in the postoperative interval. Four of these patients (11 percent) required reintubation. Increased postoperative respiratory support was more likely in patients with certain comorbidities and higher preoperative respiratory support requirements (p < 0.05). CONCLUSIONS: The authors' data suggest that immediate extubation following neonatal mandibular distraction is feasible in patients who are not intubated preoperatively. Careful consideration should be given to patients who require significant respiratory support preoperatively and in those with certain comorbidities. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Utilization of 3D MRI for the Evaluation of Sphincter Pharyngoplasty Insertion Site in Patients With Velopharyngeal Dysfunction.

Sphincter pharyngoplasty is a surgical method to treat velopharyngeal dysfunction. However, surgical failure is often noted and postoperative assessment frequently reveals low-set pharyngoplasties. Past studies have not quantified pharyngoplasty tissue changes that occur postoperatively and gaps remain related to the patient-specific variables that influence postoperative change. The purpose of this study was to utilize advanced three-dimensional imaging and volumetric magnetic resonance imaging (MRI) data to visualize and quantify pharyngoplasty insertion site and postsurgical tissue changes over time.A prospective, repeated measures design was used for the assessment of craniometric and velopharyngeal variables postsurgically. Imaging was completed across two postoperative time points. Tissue migration, pharyngoplasty dimensions, and predictors of change were analyzed across imaging time points.Significant differences were present between the initial location of pharyngoplasty tissue and the pharyngoplasty location 2 to 4 months postoperatively. The average postoperative inferior movement of pharyngoplasty tissue was 6.82 mm, although notable variability was present across participants. The pharyngoplasty volume decreased by 30%, on average.Inferior migration of the pharyngoplasty tissue was present in all patients. Gravity, scar contracture, and patient-specific variables likely interact, impacting final postoperative pharyngoplasty location. The use of advanced imaging modalities, such as 3D MRI, allows for the quantification and visualization of tissue change. There is a need for continued identification of patient-specific factors that may impact the amount of inferior tissue migration and scar contracture postoperatively.

Expanded Analysis of a Modified Enhanced Recovery Protocol in Cleft Palatoplasty.

OBJECTIVE: We have previously shown the efficacy of an enhanced recovery after surgery (ERAS) protocol in pediatric cleft palatoplasty for proof of concept (POC). We sought to validate the efficacy of ERAS when expanded to patients of variable age and complexity undergoing primary palatoplasty. MAIN OUTCOME MEASURE(S): Between April 2017 and December 2018, 100 patients were collected prospectively for the expanded assessment (ERAS2) and POC (ERAS1) and compared to historical controls both independently and in aggregate (ERAS(T)). We compared patient demographics, perioperative narcotic administration, length of stay (LOS), and rates of return to service (RTS). RESULTS: Despite increased complexity, total narcotic usage (morphine equivalents normalized per weight) during each phase of care was significantly greater in controls when compared to ERAS1, ERAS2, or ERAST, respectively (intraoperative: 0.44 mg/kg vs 0.013 mg/kg vs 0.016 mg/kg vs 0.014 mg/kg; postanesthesia care unit: 0.061 mg/kg vs 0.006 mg/kg vs 0.007 mg/kg vs 0.007 mg/kg; postoperative: 0.389 mg/kg vs 0.009 mg/kg vs 0.026 mg/kg vs 0.017 mg/kg). ERAS1 and ERAS2 groups each demonstrated a decrease in LOS (-36.6%, -26.3%) when compared to controls. Overall, application of ERAS led to a 95.7% reduction in narcotic administration and a 31.7% decrease in LOS when compared to controls. The incidence of RTS was higher in ERAS2 (13.0%) when compared to ERAS1 (2.1%) or controls (2.4%), with the strongest independent predictor being a positive perioperative respiratory viral panel (PRVP). CONCLUSIONS: Application of ERAS to palatoplasty patients of advanced age and complexity evidenced consistency with respect to decreased perioperative narcotic administration and shortened LOS. A positive PRVP was found to be an independent predictor of RTS even when ERAS was applied.

Implementation of a Modified Enhanced Recovery Protocol in Cleft Palate Repairs.

AIMS: Enhanced Recovery after Surgery (ERAS) protocols have been shown to improve patient outcomes in numerous adult surgical populations, but there are few known standards for their use in pediatric patients. To assess the effectiveness in pediatric craniofacial surgery, we present our results following the application of a modified ERAS protocol for patients undergoing primary palatoplasty. METHODS: A modified ERAS program was developed and implemented in a multidisciplinary manner. The primary components of the protocol included: (1) administration of gabapentinoids, (2) minimal perioperative narcotic use, and (3) post-operative pain control using nonnarcotic first-line agents. Fifty patients were collected prospectively, assigned to the modified ERAS protocol and compared to historic controls. We reviewed patient demographics, narcotic use, length of stay (LOS), oral intake, and complication rates. RESULTS: Between April 2017 and June 2018, 50 patients underwent palatoplasty under the modified ERAS protocol. The mean age (control: 9.7 ±â€Š2.3 months; ERAS: 9.9 ±â€Š1.6 months), weight (8.8 ±â€Š1.3 kg; 8.6 ±â€Š1.3 kg), and comorbidities did not vary between the groups. ERAS patients evidenced an increase in oral intake normalized per LOS (22.3 mL/h vs 15.4 mL/h). Total narcotic usage (morphine equivalents) during each phase of care was greater in the controls compared with ERAS (Intraop: 3.71 mg vs 0.12 mg; PACU: 0.51 mg vs 0.05 mg; Postop: 2.6 mg vs 0.07 mg). The implementation of this protocol led to a 36.6% decrease in LOS (1.83 days vs 1.16 days) without an increase in perioperative complications. CONCLUSIONS: Implementation of a modified ERAS protocol provided effective perioperative pain control allowing narcotic minimization, increased post-operative oral intake, and a shorter LOS without an increased complication rate.

The Effects of Age and Dose on Gene Expression and Segmental Bone Defect Repair After BMP-2 Delivery.

Age is a well-known influential factor in bone healing, with younger patients generally healing bone fractures more rapidly and suffering fewer complications compared with older patients. Yet the impact age has on the response to current bone healing treatments, such as delivery of bone morphogenetic protein 2 (BMP-2), remains poorly characterized. It remains unclear how or if therapeutic dosing of BMP-2 should be modified to account for age-related differences in order to minimize potential adverse effects and consequently improve patient bone-healing outcomes. For this study, we sought to address this issue by using a preclinical critically sized segmental bone defect model in rats to investigate age-related differences in bone repair after delivery of BMP-2 in a collagen sponge, the current clinical standard. Femoral defects were created in young (7-week-old) and adult (8-month-old) rats, and healing was assessed using gene expression analyses, longitudinal radiography, ex vivo micro-computed tomography (µCT), as well as torsional testing. We found that young rats demonstrated elevated expression of genes related to osteogenesis, chondrogenesis, and matrix remodeling at the early 1-week time point compared with adult rats. These early gene expression differences may have impacted long-term healing as the regenerated bones of young rats exhibited higher bone mineral densities compared with those of adult rats after 12 weeks. Furthermore, the young rats demonstrated significantly more bone formation and increased mechanical strength when BMP-2 dose was increased from 1 µg to 10 µg, a finding not observed in adult rats. Overall, these results indicate there are age-related differences in BMP-2-mediated bone regeneration, including relative dose sensitivity, suggesting that age is an important consideration when implementing a BMP-2 treatment strategy.

Human osteoblasts exhibit sexual dimorphism in their response to estrogen on microstructured titanium surfaces.

BACKGROUND: Osseointegration is dependent on the implant surface, surrounding bone quality, and the systemic host environment, which can differ in male and female patients. Titanium (Ti) implants with microstructured surfaces exhibit greater pullout strength when compared to smooth-surfaced implants and exhibit enhanced osteogenic cellular responses in vitro. Previous studies showed that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] has a greater effect on rat osteoblast differentiation on microstructured Ti compared to smooth Ti surfaces and tissue culture polystyrene (TCPS). The stimulatory effect of 17ß-estradiol (E2) on differentiation is observed in female osteoblasts on micro-rough Ti, but it is not known if male osteoblasts behave similarly in response to E2 and microtopography. This study assessed whether human male and female osteoblasts exhibit sex-specific differences in response to E2 and 1α,25(OH)2D3 when cultured on microstructured Ti surfaces. METHODS: Osteoblasts from three male and three female human donors were cultured on Ti discs with varying surface profiles: a smooth pretreatment (PT), a coarse grit-blasted/acid-etched (SLA), and an SLA surface having undergone modification in a nitrogen environment and stored in saline to maintain hydrophilicity (modSLA). Cells cultured on these surfaces were treated with E2 or 1α,25(OH)2D3. RESULTS: Male and female human osteoblasts responded similarly to microstructure although there were donor-specific differences; cell number decreased, and osteocalcin (OCN), osteoprotegerin (OPG), and latent and active transforming growth factor 1 increased on SLA and modSLA compared to TCPS. Female osteoblasts had higher alkaline phosphatase activity and OCN production than male counterparts but produced less OPG. Both sexes responded similarly to 1α,25(OH)2D3. E2 treatment reduced cell number and increased osteoblast differentiation and factor production only in female cells. CONCLUSIONS: Male and female human osteoblasts respond similarly to microstructure and 1α,25(OH)2D3 but exhibit sexual dimorphism in substrate-dependent responses to E2. E2 affected female osteoblasts, suggesting that signaling is sex-specific and surface-dependent. Donor osteoblasts varied in response, demonstrating the need to test multiple donors when examining human samples. Understanding how male and female cells respond to orthopedic biomaterials will enable greater predictability post-implantation as well as therapies that are more patient-specific.

Pediatric Dental Clinic-Associated Outbreak of Mycobacterium abscessus Infection.

BACKGROUND: Mycobacterium abscessus is an uncommon cause of invasive odontogenic infection. METHODS: M abscessus-associated odontogenic infections occurred in a group of children after they each underwent a pulpotomy. A probable case-child was defined as a child with facial or neck swelling and biopsy-confirmed granulomatous inflammation after a pulpotomy between October 1, 2013, and September 30, 2015. M abscessus was isolated by culture in confirmed case-children. Clinical presentation, management, and outcomes were determined by medical record abstraction. RESULTS: Among 24 children, 14 (58%) were confirmed case-children. Their median age was 7.3 years (interquartile range, 5.8-8.2 years), and the median time from pulpotomy to symptom onset was 74 days (range, 14-262 days). Clinical diagnoses included cervical lymphadenitis (24 [100%] of 24), mandibular or maxillary osteomyelitis (11 [48%] of 23), and pulmonary nodules (7 [37%] of 19). Each child had ≥1 hospitalization and a median of 2 surgeries (range, 1-6). Of the 24 children, 12 (50%) had surgery alone and 11 (46%) received intravenous (IV) antibiotics. Nineteen of the 24 (79%) children experienced complications, including vascular access malfunction (7 [64%] of 11), high-frequency hearing loss (5 [56%] of 9), permanent tooth loss (11 [48%] of 23), facial nerve palsy (7 [29%] of 24), urticarial rash (3 [25%] of 12), elevated liver enzyme levels (1 [20%] of 5), acute kidney injury (2 [18%] of 11), incision dehiscence/fibrosis (3 [13%] of 24), and neutropenia (1 [9%] of 11). CONCLUSIONS: M abscessus infection was associated with significant medical morbidity and treatment complications. Unique manifestations included extranodal mandibular or maxillary osteomyelitis and pulmonary nodules. Challenges in the identification of case-children resulted from an extended incubation period and various clinical manifestations. Clinicians should consider the association between M abscessus infection and pulpotomy in children who present with subacute cervical lymphadenitis. The use of treated/sterile water during pulpotomy might prevent further outbreaks.

Mandibular Osteomyelitis and Cervical Lymphadenitis Due to Mycobacterium abscessus: Surgical Management of a Pediatric Cohort With a Shared Epidemiologic Exposure.

BACKGROUND: Mycobacterium abscessus has been implicated as the cause of various infections in the setting of healthcare-related "outbreaks." Mandibular osteomyelitis caused by M abscessus is exceedingly rare, with only 1 patient reported in the literature. The authors describe the surgical management of 12 pediatric patients with M abscessus-related mandibular osteomyelitis and cervical lymphadenitis caused by exposure to contaminated water at a regional dental clinic. METHODS: Following institutional review board approval, new suspected patients were reviewed and followed prospectively. A multidisciplinary team coordinated the surgical approach, antibiotic regimen, and follow-up for each patient. RESULTS: Twelve patients (median age 7.5 years) received treatment of M abscessus infection. Eleven had mandibular osteomyelitis and underwent debridement along with extraction of affected teeth. Eight had lymphadenitis and underwent excision of involved nodes. Four patients (in whom surgical debridement was considered inadequate) received antibiotic therapy with a regimen of amikacin, cefoxitin, and azithromycin for 4 months. Nine of 12 patients have been followed for a median of 5 months (range 1-11 months); no patient has evidence of persistent clinical infection. Three of 4 patients treated with amikacin have high-frequency hearing loss. CONCLUSIONS: The authors describe a pediatric cohort with mandibular osteomyelitis and cervical lymphadenitis due to M abscessus following pulpotomy at a single dental clinic. Diagnosis required a high index of suspicion. Patients in our series had resolution of infection even without antibiotic therapy, suggesting that early complete surgical debridement and removal of affected lymph nodes can be sufficient as a sole treatment modality.

Inhibition of angiogenesis impairs bone healing in an in vivo murine rapid resynostosis model.

Biologics can improve bone formation, but may diffuse away from sites of therapeutic need. We developed a click-chemistry hydrogel that rapidly polymerizes in situ to control delivery of biologics during post-suturectomy resynostosis in 21-day-old male mice. Here, we used this model to determine the role of angiogenesis in post-suturectomy resynostosis and examine whether controlled release of angiogenesis inhibitors could delay bone regeneration. Hydrogels [DB-co-PEG/poly (TEGDMA)-co-(N3-TEGDMA)] were produced containing anti-angiogenic compounds [anti-VEGFA-antibody or hypoxia inducible factor 1α-inhibitor topotecan]. Bioactivity in vitro was assessed by tube length and branching points of endothelial cells in hydrogel-conditioned media. In vivo effects were examined 14 day post-suturectomy, based on the temporal analysis of angiogenic mRNAs during resynostosis following posterior frontal suture removal. MicroCT was used to quantify angiogenesis in contrast-agent-perfused blood vessels and bone defect size in defects receiving hydrogel, anti-VEGFA/hydrogel, or topotecan/hydrogel. Shorter endothelial tube length and less branching were seen in inhibitor-conditioned media (topotecan > AbVEGFA). In vivo, both compounds inhibited angiogenesis compared with hydrogel-only. Anti-VEGFA/hydrogel reduced resynostosis compared with empty defects, but topotecan/hydrogel blocked bone regeneration. We demonstrate that anti-angiogenic compounds can be incorporated into a spontaneously polymerizing hydrogel and remain active over 14 days in vitro and in vivo. Moreover, bone formation can be delayed by inhibiting neovascularization, suggesting possible use as a therapeutic to control resynostosis following suturectomies and potential applications in other conditions where rapid osteogenesis is not desired. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2742-2749, 2017.

Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli.

Stem cell fate has been linked to the mechanical properties of their underlying substrate, affecting mechanoreceptors and ultimately leading to downstream biological response. Studies have used polymers to mimic the stiffness of extracellular matrix as well as of individual tissues and shown mesenchymal stem cells (MSCs) could be directed along specific lineages. In this study, we examined the role of stiffness in MSC differentiation to two closely related cell phenotypes: osteoblast and chondrocyte. We prepared four methyl acrylate/methyl methacrylate (MA/MMA) polymer surfaces with elastic moduli ranging from 0.1 MPa to 310 MPa by altering monomer concentration. MSCs were cultured in media without exogenous growth factors and their biological responses were compared to committed chondrocytes and osteoblasts. Both chondrogenic and osteogenic markers were elevated when MSCs were grown on substrates with stiffness <10 MPa. Like chondrocytes, MSCs on lower stiffness substrates showed elevated expression of ACAN, SOX9, and COL2 and proteoglycan content; COMP was elevated in MSCs but reduced in chondrocytes. Substrate stiffness altered levels of RUNX2 mRNA, alkaline phosphatase specific activity, osteocalcin, and osteoprotegerin in osteoblasts, decreasing levels on the least stiff substrate. Expression of integrin subunits α1, α2, α5, αv, ß1, and ß3 changed in a stiffness- and cell type-dependent manner. Silencing of integrin subunit beta 1 (ITGB1) in MSCs abolished both osteoblastic and chondrogenic differentiation in response to substrate stiffness. Our results suggest that substrate stiffness is an important mediator of osteoblastic and chondrogenic differentiation, and integrin ß1 plays a pivotal role in this process.

Characteristics of 1616 Consecutive Dog Bite Injuries at a Single Institution.

Dog bite injuries remain a common form of pediatric trauma. This single-institution study of 1616 consecutive dog bite injuries over 4 years revealed a much higher prevalence of dog bites as compared with other similar centers. Though inpatient admission was rare (9.8%), 58% of all patients required laceration repair, primarily in the emergency department. Infants were more than 4 times as likely to be bitten by the family dog and more than 6 times as likely to be bitten in the head/neck region. Children ≤5 years old were 62% more likely to require repair; and 5.5% of all patients required an operation. Pit bull bites were implicated in half of all surgeries performed and over 2.5 times as likely to bite in multiple anatomic locations as compared to other breeds. The relatively high regional prevalence and younger age of injured patients as compared with other centers is a topic of further study but should draw attention to interventions that can minimize child risk.

Mid-Term Dental and Nerve-Related Complications of Infant Distraction for Robin Sequence.

BACKGROUND: Mandibular distraction is effective for relieving airway obstruction in Robin sequence; however, mid-term dental and nerve-related complications have not been adequately studied. METHODS: Records were reviewed for patients with a single distraction in infancy using internal devices. Follow-up was 5 years or longer. Craniofacial dysmorphic syndromes and those affecting facial nerve function were excluded. Part I involved a review of dental records, whereas Part II involved assessment of inferior alveolar and marginal mandibular nerve function in returning patients with the use of 1,1,1,2-tetrafluoroethane cold stimulation and photography, respectively. RESULTS: Eighty-five patients met inclusion criteria. Dental records were complete in 44 patients (median follow-up, 7.3 years; range, 5.4 to 13.2 years). First permanent molar injury was seen in 42 of 88 half-mouths (48 percent); 32 of 42 (76 percent) were restorable. Primary second molar damage and ankylosis were observed in 12 of 88 (14 percent) and one of 88 half-mouths (1 percent), respectively. Mandibular second premolar absence was noted unilaterally in eight of 36 patients (22 percent) and bilaterally in six of 36 patients (17 percent). A mean 1.2 ± 0.95 operative rehabilitations were required. Nerve testing was completed in 20 patients (median follow-up, 8.7 years; range, 5.5 to 13.2 years). Complete absence of cold sensation was noted in one of 40 half-mouths (2.5 percent), whereas lower lip depressor weakness was seen in six of 40 half-mouths (15 percent). CONCLUSIONS: Infant distraction is highly successful in averting tracheostomy; however, dental and nerve-related complications remain underreported. Regular follow-up with a pediatric dentist and early recognition of injury is essential. Although inferior alveolar nerve injury appears infrequent (2.5 percent), permanent lower lip depressor weakness is more common than previously reported (15 percent of sides). CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Differential spatial regulation of BMP molecules is associated with single-suture craniosynostosis.

OBJECTIVE The aim of this study was to examine messenger RNA (mRNA) levels of bone morphogenetic protein (BMP) ligands, receptors, and soluble inhibitors in cells isolated from single-suture synostoses from fused coronal, metopic, sagittal, and lambdoid sutures. METHODS Cells were isolated from bone collected from patients undergoing craniotomies at Children's Healthcare of Atlanta. Real-time polymerase chain reaction was used to examine mRNA levels in cells isolated from fused sutures or patent sutures in comparison with levels in normal bone from the same patient. RESULTS Cells isolated from fused sutures in cases of sagittal and coronal synostosis highly expressed BMP2, while cells isolated from fused metopic or lambdoid synostosis expressed high BMP4. Noggin, a BMP inhibitor, was lower in fused sutures and had high expression in patent sutures. CONCLUSIONS These results suggest that BMPs and inhibitors play a significant role in the regulation of suture fusion as well in the maintenance of patency in the normal suture.

Sphincterplasty for Velopharyngeal Insufficiency in the Child Without a Cleft-Palate: Etiologies and Speech Outcomes.

The aim of this study is to report on speech outcomes following surgery for velopharyngeal insufficiency (VPI) on a broad spectrum of patients without a cleft palate. Inclusion criteria included patients without a cleft palate operated on by a single surgeon (JKW) over a 10-year period and postoperative speech evaluation within 1 year. All patients underwent a sphincter pharyngoplasty. The main outcome measures were perceptual speech assessment using a 6-point scale (1 = none or normal, 6 = severe); velopharyngeal function (VPF) (1 = adequate, 2 = marginal, 3 =  dequate); and quantitative nasalance score. Forty children (mean age 7.5 y) were included. Eight unique conditions were identified; the most common was 22q deletion syndromes (27.5%). All patients had a deep nasopharynx, mean nasopharyngeal depth >0.67. Two novel cases are presented in each child with mosaic Trisomy 14 and ring chromosome 18 abnormality. Of all patients, 87.5% improved their postoperative hypernasality score. Preoperatively, all patients had either marginal or inadequate VPF (2 or 3). Postoperatively, 90% of patients (n = 36) achieved adequate velar function, the remainder did not improve at the first postoperative evaluation. Intelligibility and audible nasal emissions improved in between 57% and 65% of patients. Articulation proficiency was the only perceptual rating not to improve initially, but then did so on the most recent postoperative speech evaluation. This study demonstrates successful speech outcomes in a diverse group of patients. It also increases awareness of noncleft VPI amenable to surgical correction.

Osteoblast maturation on microtextured titanium involves paracrine regulation of bone morphogenetic protein signaling.

Osteoblasts are sensitive to surface microtopography and chemistry. Osteoblast differentiation and maturation are higher in vitro and bone formation and osseointegration enhanced in vivo on microstructured titanium (Ti) compared to smooth surfaces. Cells increased BMP2 expression on microtextured Ti alloy, suggesting a paracrine role in regulating osteoblast maturation. However, recent studies show that exogenous BMP2 inhibits osteoblast production of anti-inflammatory cytokines and osteocalcin, indicating that control of BMP-signaling may be involved. This study examined whether cells modulate BMP ligands, receptors, and inhibitors during osteoblast maturation on Ti, specifically focusing on the roles of BMP2 and Noggin (NOG). mRNA and protein for BMP2, BMP4, and BMP7 and receptors BMPR1A, BMPR1B, and BMPR2, and BMP inhibitors were upregulated on microtextured surfaces in comparison to smooth surfaces. Maturation on microstructured Ti was slightly enhanced with exogenous BMP2 while NOG addition inhibited osteoblast maturation. Cells with NOG knocked down significantly increased osteoblast maturation. These results demonstrate that BMP-related molecules are controlled during osteoblast maturation on microstructured Ti surfaces and that endogenous NOG is an important regulator of the process. Modifying paracrine BMP signaling may yield more robust bone formation than application of exogenous BMPs.

Rapidly polymerizing injectable click hydrogel therapy to delay bone growth in a murine re-synostosis model.

Craniosynostosis is the premature fusion of cranial sutures, which can result in progressive cranial deformations, increased intracranial pressure, and restricted brain growth. Most cases of craniosynostosis require surgical reconstruction of the cranial vault with the goal of increasing the intracranial volume and correcting the craniofacial deformities. However, patients often experience rapid post-operative bone regrowth, known as re-synostosis, which necessitates additional surgical intervention. Bone morphogenetic protein (BMP) inhibitors have tremendous potential to treat re-synostosis, but the realization of a clinically viable inhibitor-based therapeutic requires the development of a delivery vehicle that can localize the release to the site of administration. Here, we present an in situ rapidly crosslinking injectable hydrogel that has the properties necessary to encapsulate co-administered proteins and demonstrate that the delivery of rmGremlin1 via our hydrogel system delays bone regrowth in a weanling mouse model of re-synostosis. Our hydrogel is composed of two mutually reactive poly(ethylene glycol) macromolecules, which when mixed crosslink via a bio-orthogonal Cu free click reaction. Hydrogels containing Gremlin caused a dose dependent inhibition of bone regrowth. In addition to craniofacial applications, our injectable click hydrogel has the potential to provide customizable protein, small molecule, and cell delivery to any site accessible via needle or catheter.

Biphasic fusion of the murine posterior frontal suture.

BACKGROUND: Craniosynostosis is the premature fusion of cranial sutures early in development. Mice are commonly used to study the mechanisms driving both normal and pathologic cranial suture development. Despite their frequency of use as a model, the time course of bone formation and mineralization during fusion of mouse posterior frontal suture is not well defined. METHODS: To address this, C57Bl/6J mice were euthanized at ages ranging from 6 to 107 days, and the posterior frontal sutures were imaged using micro-computed tomography. Scans were analyzed with an image-processing algorithm that was previously validated with serial histology to quantify both suture fusion and mineral content. The expression profile of genes associated with key developmental time points was examined using real-time polymerase chain reaction in both the bone and the dura. RESULTS: Results demonstrate that the bones of the posterior frontal suture come together during days 10 to 20 and then increase in mineral content and volume between days 21 and 45. The onset of posterior frontal suture fusion was associated with an increase in cartilage-associated genes on day 12. Later mineralization of the suture was associated with an increase in mRNAs for osteoblast differentiation markers, bone morphogenetic proteins, and bone morphogenetic protein inhibitors. CONCLUSIONS: Complete analysis fusion posterior frontal suture shows that it occurs in a discontinuous biphasic manner. The first phase is from days 10 to 20 and involves production of cartilage. A second mineralization phase from days 21 to 45 was seen with both the imaging algorithm and changes in gene expression.

Rapid re-synostosis following suturectomy in pediatric mice is age and location dependent.

Craniosynostosis is the premature fusion of the cranial sutures early in development. If left untreated, craniosynostosis can lead to complications resulting from cranial deformities or increased intracranial pressure. The standard treatment involves calvarial reconstruction, which in many cases undergoes rapid re-synostosis. This requires additional surgical intervention that is associated with a high incidence of life threatening complications. To better understand this rapid healing, a pediatric mouse model of re-synostosis was developed and characterized. Defects (1.5mm by 2.5mm) over the posterior frontal suture were created surgically in weanling (21 days post-natal) and adolescent (50 days post-natal) C57Bl/6J mice. In addition, defects were created in the frontal bone lateral to the posterior frontal suture. The regeneration of bone in the defect was assessed using advanced image processing algorithms on micro-computed tomography scans. The genes associated with defect healing were assessed by real-time PCR of mRNA isolated from the tissue present in the defect. The results showed that the weanling mouse healed in a biphasic process with bone bridging the defect by post-operative (post-op) day 3 followed by an increase in the bone volume on day 14. In adolescent mice, there was a delay in bone bridging across the defect, and no subsequent increase in bone volume. No bridging of the defect by 14 days post-op was seen in identically sized defects placed lateral to the suture in both weanling and adolescent animals. This study demonstrates that bone regeneration in the cranium is both age and location dependent. Rapid and robust bone regeneration only occurred when the defect was created over the posterior frontal suture in immature weanling mice.