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.

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.

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.

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.

Interrelationship of cranial suture fusion, basicranial development, and resynostosis following suturectomy in twist1(+/-) mice, a murine model of Saethre-Chotzen syndrome.

The interrelationships among suture fusion, basicranial development, and subsequent resynostosis in syndromic craniosynostosis have yet to be examined. The objectives of this study were to determine the potential relationship between suture fusion and cranial base development in a model of syndromic craniosynostosis and to assess the effects of the syndrome on resynostosis following suturectomy. To do this, posterior frontal and coronal suture fusion, postnatal development of sphenooccipital synchondrosis, and resynostosis in Twist1(+/+) (WT) and Twist1(+/-) litter-matched mice (a model for Saethre-Chotzen syndrome) were quantified by evaluating µCT images with advanced image-processing algorithms. The coronal suture in Twist(+/-) mice developed, fused, and mineralized at a faster rate than that in normal littermates at postnatal days 6-30. Moreover, premature fusion of the coronal suture in Twist1(+/-) mice preceded alterations in cranial base development. Analysis of synchondrosis showed faster mineralization in Twist(+/-) mice at postnatal days 25-30. In a rapid resynostosis model, there was an inability to fuse both the midline posterior frontal suture and craniotomy defects in 21-day-old Twist(+/-) mice, despite having accelerated mineralization in the posterior frontal suture and defects. This study showed that dissimilarities between Twist1(+/+) and Twist1(+/-) mice are not limited to a fused coronal suture but include differences in fusion of other sutures, the regenerative capacity of the cranial vault, and the development of the cranial base.

Immediate mandibular distraction in mandibular hypoplasia and upper airway obstruction.

Distraction osteogenesis of the mandible has become an alternative to tracheostomy in infants and children who present with upper airway obstruction due to micrognathia. To avoid prolonged intubation during distraction, we have implemented a protocol of immediate distraction at the time of distractor placement, which results in acute airway improvement. Over 2 years, 22 patients with micrognathia and severe airway obstruction have undergone mandibular distractor placement. Indications for surgery were apnea and desaturations with feeding. Resorbable distraction devices were placed bilaterally and activated to 5 to 8 mm. Recombinant human bone morphogenetic protein 2 was placed in the gap. Distraction was implemented at postoperative day 2 at 2 mm/d. Forty-four distraction devices were placed in 22 patients (68% male, 32% female) with a mean age of 24.1 months (range, 3 days to 5.5 years). The average distance of distraction performed in the operating room was 5 mm. The average total distraction was 24 mm performed over 12 days. Overall, 89% of patients were extubated after distractor placement in the operating room. Two patients with difficult intubations were extubated 7 days later in the operating room with otolaryngology. Of the 4 tracheostomy patients, 1 patient was decannulated, whereas 3 patients are pending postoperative sleep studies. One patient had a minor wound complication. Tracheostomy and prolonged intubation in patients with mandibular hypoplasia have significant morbidity and mortality. We have implemented a successful protocol of immediate distraction in the operating room with placement of bone morphogenetic protein. Immediate distraction appears to be an effective method of avoiding postoperative intubation and tracheostomy.

Maxillary advancement in patients with severe maxillary hypoplasia: role of adjuvant stabilization techniques and materials.

BACKGROUND: Maxillary advancement in patients with orofacial clefts or craniofacial syndromes can be technically challenging. We present our experience with the use of adjunctive stabilization materials and techniques in patients undergoing single-stage maxillary advancements of more than 6.0 mm. METHODS: A retrospective review was performed of 25 patients who underwent maxillary advancements of more than 6 mm with the use of specially manufactured rigid fixation plates, allograft, tongue-and-groove locking osteotomies, and bone morphogenic protein. No patients had intermaxillary fixation or postoperative external stabilization. There were 19 patients with orofacial clefts and 6 with a craniofacial syndrome, 13 male and 12 female patients, aged from 14 to 60 years with a mean age of 19 years. Six cases represented secondary operations. The maxilla was advanced at a range of 6.0 to 17.0 mm, mean of 9 mm. All patients were followed up by the same orthodontist preoperatively and postoperatively. Patient charts were reviewed for complications, relapse, malunion, and nonunion. RESULTS: There was 1 complication requiring embolization for bleeding. Three patients (12%) developed velopharyngeal incompetence postoperatively. There was no evidence of relapse, malunion, or nonunion. No patients required a second advancement. CONCLUSIONS: The combination of specialized rigid fixation plates, allograft, tongue-and-groove locking osteotomies, and bone morphogenic protein was found to be safe and effective in preventing significant surgical relapse even after significant maxillary advancements.

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.

Use of Integra in complex pediatric wounds.

The usefulness of Integra is well described in the adult reconstructive and burn literature. There is limited documentation of its utility in the pediatric plastic surgery population. We presented 8 cases referred to us for flap coverage that were treated using Integra. These cases describe difficult wounds resulting from trauma, and congenital abnormalities. The charts of all 8 cases were retrospectively reviewed. There were 5 females and 3 newborns. The average age at coverage with Integra was 4.6 years (range, 1 day-16 years). There were 4 traumatic wounds, 2 cases of cutis aplasia, 1 myelomeningocele, and 1 case of congenitally absent cranium. The average time to coverage was 8 days, and all trauma patients underwent at least 2 prior washout procedures. The average area covered was 43 cm (range, 6-100 cm). At a mean follow-up of 14.25 months (range, 9-20 months), 7 patients' wounds had healed without need for further flap coverage. Only 1 patient required a skin graft over the Integra bed. There was 1 infection resulting in total dermal matrix loss and need for local flap reconstruction. One patient developed severe hypertrophic scarring requiring surgical revision. Integra is a reliable option in pediatric reconstruction, which may save a child the morbidity of a more extensive procedure.

Fibrin glue: a scaffold for cellular-based therapy in a critical-sized defect.

PURPOSE: Cartilage-based treatments have vast applications in plastic and reconstructive surgery, especially craniofacial constructs. Current techniques in craniofacial cartilage reconstructions greatly rely on autologous donor site harvest. Whole cartilage grafts are wrought with complications of warping, resorption, extrusion, and donor site morbidity. Percutaneous delivery of expanded chondrocytes would have the potential to expand a small quantity of autologous cells to deliver cell therapy. To deliver chondrocytes effectively, there must be a reliable medium in which chondrocytes can be kept. The purpose of this work is to highlight the utility of fibrin glue sealant, Evicel, as a suitable chondrocyte carrier in the treatment of a critical-sized defect model of nonarticular cartilage previously developed in our laboratory. METHODS: Athymic rats were separated into 2 groups: fibrin glue (n = 3) and fibrin glue + rat chondrocytes (n = 6). The animals with an empty defect were used to ensure that they responded normally to the procedure. All animals received a 3-mm full-thickness xiphoid cartilage defect characterized previously as a critical-sized defect in our laboratory (Moyer HR, Wang Y, Farooque T, et al. Tissue Eng Part A. 2010;16:2321-2330). A control animal received no xiphoid defect creation procedure. The fibrin glue group was treated with 0.5 mL of fibrin glue placed directly into the 3-mm defect. The fibrin glue/rat chondrocyte group received a mixture of 1 × 10 resting zone chondrocytes mixed with 0.5 mL of fibrin glue. Rats were euthanized at 5 weeks (35 days) and their xiphoid cartilages harvested. The xiphoids were analyzed with morphometrics through histology and microcomputed tomography. RESULTS: In the fibrin glue vehicle group, there was minimal evidence of wound healing. Xiphoid defects treated with resting zone chondrocytes in a fibrin glue carrier were significantly smaller (P = 0.002) at harvest and had significantly more glycosaminoglycan content on microcomputed tomography analysis. Thus, there was significant healing in the chondrocyte/fibrin glue group. CONCLUSION: Human fibrin sealant is an effective chondrocyte carrier and retains viable cells. Treatment of a nonarticular critical-size defect with resting zone chondrocytes embedded in a fibrin glue polymer demonstrates tissue healing.

Use of rectus abdominis muscle flap as adjunct to bladder neck closure in patients with neurogenic incontinence: preliminary experience.

PURPOSE: Vesicoureteral fistula is a well-known potential complication following bladder neck closure for neurogenic incontinence. Various maneuvers, including omental interposition, have been described to prevent this problem. Unfortunately omentum is not always available or feasible for use. We describe the surgical anatomy and use of a rectus abdominis muscle flap as an adjunctive maneuver during bladder neck closure to correct or prevent development of bladder neck fistula. MATERIALS AND METHODS: We performed a retrospective chart review of all patients at our institution undergoing rectus abdominis muscle flap by a single surgeon (EAS). Patient demographics, indications for surgery, intraoperative and postoperative complications, and long-term efficacy were assessed. Cadaveric dissection was also performed to gain a greater understanding of the surgical anatomy relevant to this procedure. RESULTS: In 6 patients with neurogenic bladder dysfunction a rectus abdominis muscle flap was interposed between the bladder neck and urethral stump at bladder neck closure. There were no intraoperative or postoperative complications associated with this procedure. At a mean followup of 45.5 months (range 18 to 120) all 6 patients were continent of urine. There have been no urinary fistulas related to use of the rectus abdominis muscle flap. Cadaveric dissections confirmed the inferior epigastric artery to be the dominant and readily mobile blood supply of the rectus abdominis muscle flap. CONCLUSIONS: The rectus abdominis muscle flap is easily harvested without significant risk of morbidity and offers a well vascularized tissue for coverage of a bladder neck closure when an omental flap is not available.

Alginate microencapsulation technology for the percutaneous delivery of adipose-derived stem cells.

BACKGROUND: Autologous fat is the ideal soft-tissue filler; however, its widespread application is limited because of variable clinical results and poor survival. Engineered fillers have the potential to maximize survival. Alginate is a hydrogel copolymer that can be engineered into spheres of <200 µm, thus facilitating mass transfer, allowing for subcutaneous injection, and protecting cells from shearing forces. METHODS: Alginate powder was dissolved in saline, and adipose-derived stem cells (ADSCs) were encapsulated (1 million cells/mL) in alginate using an electrostatic bead generator. To assess effects of injection on cell viability, microspheres containing ADSCs were separated into 2 groups: the control group was decanted into culture wells and the injection group was mixed with basal media and injected through a 21-gauge needle into culture wells. Microbeads were cultured for 3 weeks, and cell number and viability were measured weekly using electron and confocal microscopy. To assess effects of percutaneous injection in vivo, twenty-four male nude mice were randomly separated into 2 groups and injected with either empty microcapsules or ADSC-laden microcapsules. Mice were harvested at 1 and 3 months, and the implants were examined microscopically to assess bead and cell viability. RESULTS: A flow rate of 5 mL/h and an electrostatic potential of 7 kV produced viable ADSC-laden microbeads of <200 µm. There were no differences in bead morphology and ADSC viability between microcapsules placed versus injected into tissue culture plates for up to 3 weeks. Microspheres implanted in a nude mouse model show durability up to 3 months with a host response around each individual sphere. ADSCs remained viable and showed signs of mitosis. CONCLUSIONS: ADSCs can be readily cultured, encapsulated, and injected in alginate microspheres. Stem cells suspended in alginate microspheres survive in vivo and are seen to replicate in vitro.

Use of hydroxyapatite cement in pediatric craniofacial reconstructive surgery: strategies for avoiding complications.

The emergence of powdered hydroxyapatite (HA) has dramatically expanded the repertoire of reconstructive tools for craniofacial surgeons. Although several groups have reported mixed success using HA powder, to date there have been few large series retrospective reviews of HA use in an exclusively pediatric population. The purpose of our study was to assess the incidence of complications using a single surgeon's experience in an entirely pediatric cohort of patients. We present 78 pediatric patients (mean age, 9 [SD, 5.1] years; 26 girls, 52 boys) who have undergone craniofacial reconstruction with HA powder in the form of Mimix or BoneSource (mean, 57.3 [SD, 27.9] g). From this cohort, we discuss in detail 7 patients who experienced complications after their reconstruction with HA. These complications were related to trauma, infection, and exposure. Of these 7 patients with problems, 6 required eventual HA removal. In addition, all 7 patients who had complications after HA reported having a traumatic event with respect to their cranial reconstruction before presenting with a complication. Our series concludes that HA powder is a safe and effective material for use in pediatric craniofacial reconstruction. When certain principles are not violated, meticulous hemostasis and surgical planning are of paramount importance to reduce the incidence of seroma, exposure, and infection of the overlying HA placement. However, should these complications arise, prompt removal of HA is usually necessary.

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.

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.

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.